Eye disease Study

Added: Mar 23, 2018 7:28 pm Statement of Work
Clinical and initial laboratory services for ascertainment of patients with inherited eye diseases in Pakistan

I. Background Information and Description of Acquisition

Background

a. The National Eye Institute's (NEI) Division of Intramural Research (DIR) conducts a multidisciplinary investigation of a wide range of blinding and disabling eye diseases, including immunological disorders, diabetic retinopathy, autosomal recessive congenital cataract (arCC), glaucoma, and retinal degenerations. Investigators in the NEI have been studying autosomal recessive retinitis pigmentosa (arRP), a hereditary, progressive retinal degeneration ultimately resulting in blindness. There are several forms of RP, each of which is caused by a specific, but in most instances unknown, a genetic defect. Identifying these defects is crucial to the development of effective diagnosis and treatment for RP. Investigators in the NEI have also been studying inherited cataracts, the most common cause of blindness worldwide, in a similar fashion.

b. A large number of families in Pakistan have members who have been diagnosed with a recessive form of retinitis pigmentosa or cataracts. The population of Pakistan forms a distinct genetic group. Because of their consanguinity as well as the tendency for extended families to live in close proximity, these families provide a unique opportunity for scientists to identify the genetic defect causing this form of retinitis pigmentosa or inherited cataracts. Since the collection, assessment, and supply of pedigrees for genetic analysis is of direct benefit to the NEI, a contract is an appropriate instrument for this procurement.

c. In the initial years of this contract, NEI and Dr. Riazuddin's laboratory previously at the National Center for Excellence in Molecular Biology (CEMB) and now also at Allama Iqbal Medical Research Centre has analyzed 336 families with arRP and 151 families with arCC. Of these 487 families, 382 were estimated to be capable of yielding lod scores greater than 3 by themselves. Using these families we have mapped 48 to cataract loci (7 novel), identifying mutations in 43 families, and 11 to arRP loci (4 novel) and identified the gene an mutation in 96. Mapping efforts continue on 348 families, 382 of which can produce a lod score over 3 independently. These results are summarized in the following table.

Cataracts RP Sum
Total # of families ascertained 151 336 487
Mapped (to known and new loci) 48 111 159
Families mappable independently but yet to be mapped 37 40 87
Families unmappable independently (need to be paired) 58 147 205

Genes Identified (known and new) 43 96 139
Manuscripts (published) 80 52 132

Summarizing the progress with families recruited from Pakistan to-date

These results and those in our recent summary papers1; 2 suggest that still roughly one third to half of the genes causing arRP and arCC in the Pakistani population have been identified, and that it is likely that collection of new families will result in identification of novel RP or CC loci in half of those capable of being mapped by themselves. This assessment is also supported by our recent results in southern India.3 Also, as additional families are collected, it seems likely that two or more families will be identified mapping to the same locus, although this will have to withstand analysis using the admixture test. In addition, as the CEMB begins to collect families from more distant regions in Pakistan, new gene pools should be tapped. Thus, this contract has been productive in terms of identifying new genetic loci of arCC and arRP, and shows every indication of continuing to be a rich source of families with diseases caused by novel loci.

II. Purpose

Scientists at the National Eye Institute (NEI) propose to continue this study in which they will obtain blood samples from family members of 100 affected families over a four year period and conduct the research analyses necessary to isolate and identify the defect. This project will require that individual family members be screened and clinically evaluated, that family pedigrees be developed, and forwarded to the NEI. Since the NEI does not have the resources necessary to conduct the on-site evaluations and develop family pedigrees, the NEI requests the services of a contractor, who must have an M.D. or Ph.D. degree and specialized training and experience in the medical genetics of retinal degenerations.

III. Tasks

Independently, and not as an agent of the government, the contractor will be responsible for the conduct of on-site assessments of families with a history of recessive RP or hereditary cataract. The contractor will screen all available family members to identify affected and unaffected individuals and will take detailed medical histories, from which family pedigrees will be developed. The contractor will be responsible for obtaining ophthalmic examinations for individuals. The contractor will also screen patient's blood samples for mutations in genes known to cause RP and hereditary cataract. For these activities, the contractor must have access to a fully equipped and appropriately staffed eye clinic. The contractor will be responsible for properly packaging and shipping blood and/or DNA specimens to the National Eye Institute for analysis.

1. The contractor will be responsible for:

a. Ascertainment of families with a history of recessive retinitis pigmentosa or hereditary cataracts.

b. The conduct of on-site assessments of families with a history of recessive retinitis pigmentosa or cataracts. The contractor will screen all available family members to identify affected and unaffected individuals and will take detailed medical histories, from which family pedigrees will be developed.

c. Performing or supervising ophthalmic examinations from these individuals. These examinations will include one or more of the following:

1) Visual function testing
2) Perimetry
3) Fundoscopic examination
4) Electroretinography
5) Humphries peripheral field examination
6) Other tests as mutually agreed upon by the NEI and contractor

d. Collecting blood samples for DNA isolation/transformation and analysis at the NEI and optionally at the National Centre of Excellence in Molecular Biology at the University of the Punjab.

e. Shipment of non-hemolyzed blood samples or DNA samples to the NEI by
Federal Express or other comparable express mail service.

1) Preservation, packaging, and packing shall be used to afford adequate protection against corrosion, deterioration, and physical damage during shipment. The NEI will provide packaging if requested.
2) Standard commercial marking shall be used for shipping, with each container labeled with the contractor's name and address and the total number of samples in the shipment.
3) Each blood sample shall be labeled with the individual's name, date of birth, and the date the sample was drawn.
4) Each DNA sample, 100 micrograms of DNA in TE, should be labeled with an arbitrary laboratory identifier, and information as in 3) should be included in accompanying paperwork for that identifier.
5) Blood samples from one affected individual in each family should arrive at the NEI within 3 days after blood drawing, if possible.
6) At the time of blood drawing, a small amount of blood should be spotted on a Guthrie card, which should be sent with the blood or DNA sample.

2. The contractor will have the option of performing initial assessments of samples collected from each family with respect to linkage to genetic loci known to be associated with retinitis pigmentosa or hereditary cataract.

a. This assessment will consist of genotyping using markers in proximity to known autosomal recessive retinitis pigmentosa loci or cataract (Please see appendixes I & II).

b. The NEI will supply all oligonucleotide primers for this testing, and any additional analysis agreed to by both parties.

c. Other than these tests above performed by the contractor and other tests specifically agreed to by both the contractor and the NEI, the contractor and NEI will have exclusive use of samples from these patients.

d. The initial loci to be screened will include all known inherited cataract and/or retinitis pigmentosa loci.

Additional loci may become known in the course of this project and will be added to the above lists.

3. It is expected that as part of this agreement, one individual from Dr. Riazuddin's laboratory will train in the NEI or a collaborator mutually agreeable to the NEI and the contractor as a Fogarty Fellow for at least the period of this contract. This fellow will have the option of analyzing the samples collected in Pakistan or on another project mutually agreeable to all parties.

IV. Reports

1. At the time of delivery of samples from each family the contractor will also send, either as a hardcopy or electronic file:

a. A completed pedigree is drawn either by hand or with a computerized program such as Cyrillic.

b. Completed history and examination forms describing the clinical findings.

c. Copies of any laboratory results available at that time such as original data, ABI exported to text files, or linkage profiles or results.

2. At the time of completion and before the end of the contract, genotyping data and/or linkage results of the initial screen for known autosomal recessive RP loci and the genome-wide scans.

3. Publications arising from this project will include authorship by both the NEI and contractor and others by mutual agreement. Decisions regarding publication and authorship will be by mutual agreement.

V. Other Contractor Requirements

1. Before initiation of sample collection, the contractor must submit paperwork sufficient to demonstrate an existing FWA with the National Centre of Excellence in Molecular Biology at the University of the Punjab as required by the NEI Institutional Review Board and the NIH Office of Human Research Protections, U.S. Department of Health and Human Services. In addition, the contractor must provide annual documentation of approval by the CEMB IRB of a human research protocol covering this project. These are necessary to have the contractor listed as a collaborator on the CNS IRB protocol supporting this project.

 

The project will be carried out in three stages each year, each independent of the others. The initial stage will be carried out in 3-4 months and will consist of a collection of at least 20 families. The second will also be carried out in 3-4 months and will consist of a collection of at least 15 families. The third will be carried out over the remainder of the first year and will consist of recruitment of the remaining 15 families. Funding for the

VII. Facts and Reasons to Justify Other than Full and Open Competition

Pakistan is a developing country, with a population of 170 million and poor medical infrastructure. A large number of families in Pakistan have members who have been diagnosed with a recessive form of retinitis pigmentosa. The population of Pakistan forms several distinct genetic groups. Because of their consanguinity as well as the tendency for extended families to live in close proximity, these families provide a unique opportunity for scientists to identify the genetic defects causing this form of retinitis pigmentosa. This project will require that individual family members be screened and clinically evaluated, that family pedigrees be developed, and forwarded to the NEI. Since the NEI does not have the resources necessary to conduct the on-site evaluations and develop family pedigrees, the NEI requests the services of a contractor, who must have an M.D. or Ph.D. degree and specialized training and experience in the medical genetics of retinal degenerations.
Allama Iqbal Medical College (AIMC) was established in 1975 and is now one of the leading medical teaching and research institutions with an attached 1200 bed hospital that provides free healthcare to the general public. The most notable departments include ophthalmology, otolaryngology, pediatrics, gynecology, neurosciences, orthopedics, oncology, and radiotherapy. There are three units of the gynecology department which treats about 120 new births every day. As a consequence, the hospital provides a very large and rich resource of clinical material which is available to the clinicians/researchers after obtaining explicit consent of the donors. There are four units of the ophthalmology department which treats about 250 patients every day, mainly from the Punjab area but also from other provinces of Pakistan.
In Pakistan, medical research is done predominantly but not exclusively in general universities. In 2009, the government decided to set-up a world-class research Centre namely Allama Iqbal Medical Research Centre under the leadership of Prof. Riazuddin, Founding Director of Centre of Excellence in Molecular Biology at University of the Punjab, Lahore. At the 10th Convocation held on February 06, 2010, the Prime Minister of Pakistan approved the establishment of Allama Iqbal Medical Research Centre (AIMRC) with first-rate facilities for basic and clinical research in those areas in which the hospital has leading departments.
Professor S. Riazuddin has moved from CEMB to AIMRC with all materials and equipment and is gradually expanding his program on genetic diseases. At CEMB his primary focus was on hearing and vision impairment, however, at AIMRC he has expanded the scope of his work to include other common genetic diseases in Pakistan including mental retardation.
Prof. Riazuddin has developed mutually beneficial collaboration with a number of leading laboratories including Tom Friedman's Laboratory at NIDCD (hearing impairment); with Dr. H.H. Ropers at Max Planck Institute, Berlin, and Dr. Hans Van Bokhoven at Redbond University, Netherlands (mental retardation). His research on mental retardation is supported by Economic European Communities (EEC) and International Centre for Genetic Engineering and Biotechnology (ICGEB), Trieste, Italy. His other research projects are supported by the Pak-US Science Program. His previous research support includes USNSF and Rockefeller Foundation's program in biotechnology.

AIMRC is advised by a group of illustrious scientists with whom you refer to in case you may need to know more about the work at CEMB.

• Prof. Richard J. Roberts (Nobel Laureate), New England Biolabs., Inc., 32 Tozer Road, Beverly, MA 01915-5510, USA. (T.N.508-927-3382).
• Prof. Roger McMacken, Department of Biochemistry, School of Hygiene and Public Health, 615 N. Wolf Street, Baltimore, MD 21205 USA. (T.N.410-955-3671)
• Prof. Lawrence A. Loeb, Director, Joseph Cottstein Memorial Cancer Res. Lab., Health Sciences Building, K-Block, University of Washington, Seattle, WA98185, USA. (T.N.206-435-6015)
• Prof. Marc Van Montagu, VIB Rijvisschestraat 120, B-9052 Zwijnaarde, Belgium. (T.N.32-9-2648726)
• Prof. M. Ashraf, Department of Pathology & Laboratory Medicine, University of Cincinnati, P.O. Box 670529, 231 Bethesda Avenue, Cincinnati, OH 45267-0529, (T.N.513-558-4500)
• Prof. Ken-ichi Arai, Professor Emeritus, The University of Tokyo, Japan.
• Prof. Jeongbin Yim, President A-IMBN, Bio-MAX Institute. Seoul National University, Seoul 151-742, Korea
Other bodies of the AIMRC include an Academic Council (AC), a Board of Studies (BOS) and Institutional Review Board (IRB). The IRB assesses the selection of subjects and risk-benefit criteria and appropriate elements of informed functions before the research. If special populations are involved, their welfare, risk assessment, and consent language are critically evaluated. Institutional policies, equipment, staff, local laws, professional and community standards are also considered. The IRB conducts initial and continuing reviews of research activities involving human/animal subjects by reviewing research protocols and reports its findings to the investigators/institution. The IRB constitution is as under:
• Dr. Fazle Majid Khan, Ex-Professor of Zoology and Resident Officer, University of the Punjab, Lahore.
• Mr. Muhammad Zafar, Human Rightists, Advocate, Supreme Court, Islamabad.
• Dr. Fauzia Iqbal Butt, Hematologists, Allama Iqbal Medical College, Lahore.
• Dr. Bushra Choughry, Biotechnologist, Centre for Applied Molecular Biology, Lahore, Pakistan.
• Dr. Muhammad Yaqub, Senior Scientist, PCSIR Laboratories, Lahore.

Professor S. Riazuddin's laboratory represents one of the best places for molecular biological research, in this part of the world. There are three other laboratories, namely the National Institute for Biotechnology and Genetic Engineering (NIBGE), Faisalabad; Abdul Qadir Khan Research Laboratories (AQRL), Islamabad, Centre for Genetics, Karachi University, Karachi; engaged in molecular biological work, however, none of these is doing research comparable in scope and quality to that being pursued at Professor Riazuddin's laboratory, at AIMRC, University of Health Sciences, Lahore.
Professor S. Riazuddin's Laboratory is working on the frontiers of molecular biological research through collaborations with laboratories in Europe and USA. Most notable of these endeavors are collaborations with Lawrence Grossman, Johns Hopkins University, Baltimore; Richard J. Roberts (Nobel Laureate) previously at Cold Spring Harbor Labs; Lawrence Loeb; Milton P. Gordon and Eugene Nester at University of Washington, Seattle; Marc Van Montagu, presently at VIB Rijvisschestraat, Zwijnaarde, Belgium. These collaborations are built on the complementary strengths of participating laboratories designed to advance common goals. The US National Science Foundation (International Program), the Rockefeller Foundation and the National Research Council have funded USA-CEMB collaboration.
In addition to the NEI-CEMB experience over the last years and described above, researchers in the laboratories of molecular genetics at the NIDCD/NIH and Professor Riazuddin's laboratory, at Lahore, Pakistan are working together in mapping genes in many families from Pakistan. A protocol entitled non-syndromic hereditary hearing impairment -- gene mapping has been approved for this study. The protocol number is OH93-N-016. DNA samples from many extended families have been collected under this protocol. The joint venture started in 1996 and has proved extremely successful. During the last year, the joint work has resulted in 69 publications on inherited deafness and other areas of genetics.
Laboratory Research with NIDCD/NIH is being implemented through the following to whom you may refer in case you need to know more about CEMB.
• Dr. Thomas B. Friedman, Laboratory of Molecular Genetics NIDCD/NIH, Maryland 20850, USA (T.N. 301-402-4162)
• Dr. Dennis Drayna, Laboratory of Molecular Genetics NIDCD/NIH, Maryland 20850, USA. (T.N. 301-402-4162)
• Dr. Andrew Griffith, Laboratory of Molecular Genetics NIDCD/NIH, Maryland 20850, USA. (T.N. 301-402-4162)

Thus, Dr. Riazuddin has over 15 years of experience working on collaborations with NIH investigators both in NIDCD and NEI. He is clearly an accomplished molecular biologist as can be seen from his Curriculum Vitae. He worked for a number of years in England, USA, and Sweden before returning to Pakistan to develop a solid and definitive program of molecular biological research and teaching in his native country. He set-up the first molecular biology laboratory in the country in Faisalabad to work on DNA repair enzymes in the late 70s. In 1985, he moved to Lahore as the founding Director of the Centre of Excellence in Molecular Biology where he has worked with exemplary dedication to develop the Centre into an excellent place of learning in that part of the world. Young researcher from countries of the region including India, Iran, Turkey, Egypt, Jordan, Nepal, Bangladesh, and Malaysia come to work for sabbatical assignments. As a result, more than 200 scientists have passed through the corridors of the Centre during the last ten years. In summary, Dr. Riazuddin has over 21 years of experience working in molecular genetics and molecular biology.
Dr. Riazuddin has successfully used the local genetic resource and discovered several new Bacillus thuringiensis genes, restrictions enzymes, and nonsyndromic deafness genes. To overcome the inherent difficulties of practicing quality molecular biological research in a developing country, he has built collaborative endeavors with US laboratories where the best of science is done. These collaborations are built on complementary strengths to achieve common goals. The previous experience of researchers at Riazuddin's laboratory, the success of previous collaborations as evident from the publications that have resulted from his collaboration with both NIDCD and NEI (Appendix III), the existing laboratory infrastructure at Riazuddin's laboratory, and the relatedness of its ongoing program to the proposed research fully justify the selection of Dr. Riazuddin's laboratory as the possible collaborating laboratory in Pakistan. No other laboratory in Pakistan offers similar potential, to ensure the success of the proposed collaborative program.
 
Appendix I: Peer Reviewed Publications of Dr. Riazuddin in collaboration with NEI & NIDCD

1. Riazuddin,S., Castelein,C.M., Ahmed,Z.M., Lalwani,A.K., Mastroianni,M.A., Naz,S., Smith,T.N., Liburd,N.A., Friedman,T.B., Griffith,A.J., et al. (2000) Dominant modifier DFNM1 suppresses recessive deafness DFNB26. Nat. Genet., 26, 431-434.
2. Friedman,T., Battey,J., Kachar,B., Riazuddin,S., Noben-Trauth,K., Griffith,A., Wilcox,E. (2000) Modifier genes of hereditary hearing loss. Curr. Opin. Neurobiol., 10, 487-493.
3. Liburd,N., Ghosh,M., Riazuddin,S., Naz,S., Khan,S., Ahmed,Z., Riazuddin,S., Liang,Y., Menon,P.S., Smith,T., et al. (2001) Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith-Magenis syndrome. Hum. Genet., 109, 535-541.
4. Ben-Yosef,T., Wattenhofer,M., Riazuddin,S., Ahmed,Z.M., Scott,H.S., Kudoh,J., Shibuya,K., Antonarakis,S.E., Bonne-Tamir,B., Radhakrishna,U., et al. (2001) Novel mutations of TMPRSS3 in four DFNB8/B10 families segregating congenital autosomal recessive deafness. J. Med. Genet., 38, 396-400.
5. Ahmed,Z.M., Riazuddin,S., Bernstein,S.L., Ahmed,Z., Khan,S., Griffith,A.J., Morell,R.J., Friedman,T.B., Riazuddin,S., Wilcox,E.R. (2001) Mutations of the protocadherin gene PCDH15 cause Usher syndrome type 1F. Am. J. Hum. Genet., 69, 25-34.
6. Wilcox,E.R., Burton,Q.L., Naz,S., Riazuddin,S., Smith,T.N., Ploplis,B., Belyantseva,I., Ben-Yosef,T., Liburd,N.A., Morell,R.J., et al. (2001) Mutations in the gene encoding tight junction claudin-14 cause autosomal recessive deafness DFNB29. Cell, 104, 165-172.
7. Bork,J.M., Peters,L.M., Riazuddin,S., Bernstein,S.L., Ahmed,Z.M., Ness,S.L., Polomeno,R., Ramesh,A., Schloss,M., Srisailpathy,C.R., et al. (2001) Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am. J. Hum. Genet., 68, 26-37.
8. Riazuddin,S., Ahmed,Z.M., Friedman,T.B., Griffith,A.J., Riazuddin,S., Wilcox,E.R. (2002) Genetic modifiers of hereditary hearing loss. Adv. Otorhinolaryngol., 61, 224-229.
9. Ahmed,Z.M., Riazuddin,S., Friedman,T.B., Riazuddin,S., Wilcox,E.R., Griffith,A.J. (2002) Clinical manifestations of DFNB29 deafness. Adv. Otorhinolaryngol., 61, 156-160.
10. Bork,J.M., Morell,R.J., Khan,S., Riazuddin,S., Wilcox,E.R., Friedman,T.B., Griffith,A.J. (2002) Clinical presentation of DFNB12 and Usher syndrome type 1D. Adv. Otorhinolaryngol., 61, 145-152.
11. Friedman,T.B., Hinnant,J.T., Ghosh,M., Boger,E.T., Riazuddin,S., Lupski,J.R., Potocki,L., Wilcox,E.R. (2002) DFNB3, spectrum of MYO15A recessive mutant alleles and an emerging genotype-phenotype correlation. Adv. Otorhinolaryngol., 61, 124-130.
12. Naz,S., Giguere,C.M., Kohrman,D.C., Mitchem,K.L., Riazuddin,S., Morell,R.J., Ramesh,A., Srisailpathy,S., Deshmukh,D., Riazuddin,S., et al. (2002) Mutations in a novel gene, TMIE, are associated with hearing loss linked to the DFNB6 locus. Am. J. Hum. Genet., 71, 632-636.
13. Ahmed,Z.M., Smith,T.N., Riazuddin,S., Makishima,T., Ghosh,M., Bokhari,S., Menon,P.S., Deshmukh,D., Griffith,A.J., Riazuddin,S., et al. (2002) Nonsyndromic recessive deafness DFNB18 and Usher syndrome type IC are allelic mutations of USHIC. Hum. Genet., 110, 527-531.
14. Astuto,L.M., Bork,J.M., Weston,M.D., Askew,J.W., Fields,R.R., Orten,D.J., Ohliger,S.J., Riazuddin,S., Morell,R.J., Khan,S., et al. (2002) CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness. Am. J. Hum. Genet., 71, 262-275.
15. Kurima,K., Peters,L.M., Yang,Y., Riazuddin,S., Ahmed,Z.M., Naz,S., Arnaud,D., Drury,S., Mo,J., Makishima,T., et al. (2002) Dominant and recessive deafness caused by mutations of a novel gene, TMC1, required for cochlear hair-cell function. Nat. Genet., 30, 277-284.
16. Ahmed,Z.M., Riazuddin,S., Ahmad,J., Bernstein,S.L., Guo,Y., Sabar,M.F., Sieving,P., Riazuddin,S., Griffith,A.J., Friedman,T.B., et al. (2003) PCDH15 is expressed in the neurosensory epithelium of the eye and ear and mutant alleles are responsible for both USH1F and DFNB23. Hum. Mol. Genet., 12, 3215-3223.
17. Friedman,T.B., Schultz,J.M., Ben-Yosef,T., Pryor,S.P., Lagziel,A., Fisher,R.A., Wilcox,E.R., Riazuddin,S., Ahmed,Z.M., Belyantseva,I.A., Griffith,A.J. (2003) Recent advances in the understanding of syndromic forms of hearing loss. Ear Hear., 24, 289-302.
18. Naz,S., Alasti,F., Mowjoodi,A., Riazuddin,S., Sanati,M.H., Friedman,T.B., Griffith,A.J., Wilcox,E.R., Riazuddin,S. (2003) Distinctive audiometric profile associated with DFNB21 alleles of TECTA. J. Med. Genet., 40, 360-363.
19. Ahmed,Z.M., Morell,R.J., Riazuddin,S., Gropman,A., Shaukat,S., Ahmad,M.M., Mohiddin,S.A., Fananapazir,L., Caruso,R.C., Husnain,T., et al. (2003) Mutations of MYO6 are associated with recessive deafness, DFNB37. Am. J. Hum. Genet., 72, 1315-1322.
20. Ahmed,Z.M., Li,X.C., Powell,S.D., Riazuddin,S., Young,T.L., Ramzan,K., Ahmad,Z., Luscombe,S., Dhillon,K., MacLaren,L., et al. (2004) Characterization of a new full length TMPRSS3 isoform and identification of mutant alleles responsible for nonsyndromic recessive deafness in Newfoundland and Pakistan. BMC. Med. Genet., 5, 24.
21. Naz,S., Griffith,A.J., Riazuddin,S., Hampton,L.L., Battey,J.F., Jr., Khan,S.N., Riazuddin,S., Wilcox,E.R., Friedman,T.B. (2004) Mutations of ESPN cause autosomal recessive deafness and vestibular dysfunction. J. Med. Genet., 41, 591-595.
22. Zhang,Q., Zulfiqar,F., Riazuddin,S.A., Xiao,X., Ahmad,Z., Riazuddin,S., Hejtmancik,J.F. (2004) Autosomal recessive retinitis pigmentosa in a Pakistani family mapped to CNGA1 with identification of a novel mutation. Mol. Vis., 10, 884-889.
23. Shaikh,R.S., Ramzan,K., Nazli,S., Sattar,S., Khan,S.N., Riazuddin,S., Ahmed,Z.M., Friedman,T.B., Riazuddin,S. (2005) A new locus for nonsyndromic deafness DFNB51 maps to chromosome 11p13-p12. Am. J. Med. Genet. A, 138, 392-395.
24. Ahmad,J., Khan,S.N., Khan,S.Y., Ramzan,K., Riazuddin,S., Ahmed,Z.M., Wilcox,E.R., Friedman,T.B., Riazuddin,S. (2005) DFNB48, a new nonsyndromic recessive deafness locus, maps to chromosome 15q23-q25.1. Hum. Genet., 116, 407-412.
25. Ramzan,K., Shaikh,R.S., Ahmad,J., Khan,S.N., Riazuddin,S., Ahmed,Z.M., Friedman,T.B., Wilcox,E.R., Riazuddin,S. (2005) A new locus for nonsyndromic deafness DFNB49 maps to chromosome 5q12.3-q14.1. Hum. Genet., 116, 17-22.
26. Zhang,Q., Zulfiqar,F., Riazuddin,S.A., Xiao,X., Yasmeen,A., Rogan,P.K., Caruso,R., Sieving,P.A., Riazuddin,S., Hejtmancik,J.F. (2005) A variant form of Oguchi disease mapped to 13q34 associated with partial deletion of GRK1 gene. Mol. Vis., 11, 977-985.
27. Zhang,Q., Zulfiqar,F., Xiao,X., Riazuddin,S.A., Ayyagari,R., Sabar,F., Caruso,R., Sieving,P.A., Riazuddin,S., Hejtmancik,J.F. (2005) Severe autosomal recessive retinitis pigmentosa maps to chromosome 1p13.3-p21.2 between D1S2896 and D1S457 but outside ABCA4. Hum. Genet., 118, 356-365.
28. Riazuddin,S.A., Zulfiqar,F., Zhang,Q., Sergeev,Y.V., Qazi,Z.A., Husnain,T., Caruso,R., Riazuddin,S., Sieving,P.A., Hejtmancik,J.F. (2005) Autosomal recessive retinitis pigmentosa is associated with mutations in RP1 in three consanguineous Pakistani families. Invest Ophthalmol. Vis. Sci., 46, 2264-2270.
29. Riazuddin,S.A., Yasmeen,A., Yao,W., Sergeev,Y.V., Zhang,Q., Zulfiqar,F., Riaz,A., Riazuddin,S., Hejtmancik,J.F. (2005) Mutations in betaB3-crystallin associated with autosomal recessive cataract in two Pakistani families. Invest Ophthalmol. Vis. Sci., 46, 2100-2106.
30. Riazuddin,S.A., Yasmeen,A., Zhang,Q., Yao,W., Sabar,M.F., Ahmed,Z., Riazuddin,S., Hejtmancik,J.F. (2005) A new locus for autosomal recessive nuclear cataract mapped to chromosome 19q13 in a Pakistani family. Invest Ophthalmol. Vis. Sci., 46, 623-626.
31. Riaz,N., Steinberg,S., Ahmad,J., Pluzhnikov,A., Riazuddin,S., Cox,N.J., Drayna,D. (2005) Genomewide significant linkage to stuttering on chromosome 12. Am. J. Hum. Genet., 76, 647-651.
32. Riazuddin,S., Ahmed,Z.M., Fanning,A.S., Lagziel,A., Kitajiri,S., Ramzan,K., Khan,S.N., Chattaraj,P., Friedman,P.L., Anderson,J.M., et al. (2006) Tricellulin is a tight-junction protein necessary for hearing. Am. J. Hum. Genet., 79, 1040-1051.
33. Ahmed,Z.M., Goodyear,R., Riazuddin,S., Lagziel,A., Legan,P.K., Behra,M., Burgess,S.M., Lilley,K.S., Wilcox,E.R., Riazuddin,S., et al. (2006) The tip-link antigen, a protein associated with the transduction complex of sensory hair cells, is protocadherin-15. J. Neurosci., 26, 7022-7034.
34. Shabbir,M.I., Ahmed,Z.M., Khan,S.Y., Riazuddin,S., Waryah,A.M., Khan,S.N., Camps,R.D., Ghosh,M., Kabra,M., Belyantseva,I.A., et al. (2006) Mutations of human TMHS cause recessively inherited non-syndromic hearing loss. J. Med. Genet., 43, 634-640.
35. Riazuddin,S., Khan,S.N., Ahmed,Z.M., Ghosh,M., Caution,K., Nazli,S., Kabra,M., Zafar,A.U., Chen,K., Naz,S., et al. (2006) Mutations in TRIOBP, which encodes a putative cytoskeletal-organizing protein, are associated with nonsyndromic recessive deafness. Am. J. Hum. Genet., 78, 137-143.
36. Kitajiri,S.I., McNamara,R., Makishima,T., Husnain,T., Zafar,A.U., Kittles,R.A., Ahmed,Z.M., Friedman,T.B., Riazuddin,S., Griffith,A.J. (2007) Identities, frequencies and origins of TMC1 mutations causing DFNB7/B11 deafness in Pakistan. Clin. Genet., 72, 546-550.
37. Ain,Q., Nazli,S., Riazuddin,S., Jaleel,A.U., Riazuddin,S.A., Zafar,A.U., Khan,S.N., Husnain,T., Griffith,A.J., Ahmed,Z.M., et al. (2007) The autosomal recessive nonsyndromic deafness locus DFNB72 is located on chromosome 19p13.3. Hum. Genet., 122, 445-450.
38. Nal,N., Ahmed,Z.M., Erkal,E., Alper,O.M., Luleci,G., Dinc,O., Waryah,A.M., Ain,Q., Tasneem,S., Husnain,T., et al. (2007) Mutational spectrum of MYO15A: the large N-terminal extension of myosin XVA is required for hearing. Hum. Mutat., 28, 1014-1019.
39. Khan,S.Y., Ahmed,Z.M., Shabbir,M.I., Kitajiri,S., Kalsoom,S., Tasneem,S., Shayiq,S., Ramesh,A., Srisailpathy,S., Khan,S.N., et al. (2007) Mutations of the RDX gene cause nonsyndromic hearing loss at the DFNB24 locus. Hum. Mutat., 28, 417-423.
40. Khan,S.Y., Riazuddin,S., Tariq,M., Anwar,S., Shabbir,M.I., Riazuddin,S.A., Khan,S.N., Husnain,T., Ahmed,Z.M., Friedman,T.B., Riazuddin,S. (2007) Autosomal recessive nonsyndromic deafness locus DFNB63 at chromosome 11q13.2-q13.3. Hum. Genet., 120, 789-793.
41. Butt,T., Yao,W., Kaul,H., Xiaodong,J., Gradstein,L., Zhang,Y., Husnain,T., Riazuddin,S., Hejtmancik,J.F., Riazuddin,S.A. (2007) Localization of autosomal recessive congenital cataracts in consanguineous Pakistani families to a new locus on chromosome 1p. Mol. Vis., 13, 1635-1640.
42. Zhang,Q., Zulfiqar,F., Xiao,X., Riazuddin,S.A., Ahmad,Z., Caruso,R., MacDonald,I., Sieving,P., Riazuddin,S., Hejtmancik,J.F. (2007) Severe retinitis pigmentosa mapped to 4p15 and associated with a novel mutation in the PROM1 gene. Hum. Genet., 122, 293-299.
43. Ahmed,Z.M., Kjellstrom,S., Haywood-Watson,R.J., Bush,R.A., Hampton,L.L., Battey,J.F., Riazuddin,S., Frolenkov,G., Sieving,P.A., Friedman,T.B. (2008) Double homozygous waltzer and Ames waltzer mice provide no evidence of retinal degeneration. Mol. Vis., 14, 2227-2236.
44. Ahmed,Z.M., Masmoudi,S., Kalay,E., Belyantseva,I.A., Mosrati,M.A., Collin,R.W., Riazuddin,S., Hmani-Aifa,M., Venselaar,H., Kawar,M.N., et al. (2008) Mutations of LRTOMT, a fusion gene with alternative reading frames, cause nonsyndromic deafness in humans. Nat. Genet., 40, 1335-1340.
45. Ahmed,Z.M., Riazuddin,S., Aye,S., Ali,R.A., Venselaar,H., Anwar,S., Belyantseva,P.P., Qasim,M., Riazuddin,S., Friedman,T.B. (2008) Gene structure and mutant alleles of PCDH15: nonsyndromic deafness DFNB23 and type 1 Usher syndrome. Hum. Genet., 124, 215-223.
46. Riazuddin,S., Nazli,S., Ahmed,Z.M., Yang,Y., Zulfiqar,F., Shaikh,R.S., Zafar,A.U., Khan,S.N., Sabar,F., Javid,F.T., et al. (2008) Mutation spectrum of MYO7A and evaluation of a novel nonsyndromic deafness DFNB2 allele with residual function. Hum. Mutat., 29, 502-511.
47. Collin,R.W., Kalay,E., Tariq,M., Peters,T., van der,Z.B., Venselaar,H., Oostrik,J., Lee,K., Ahmed,Z.M., Caylan,R., et al. (2008) Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35. Am. J. Hum. Genet., 82, 125-138.
48. Firasat,S., Riazuddin,S.A., Hejtmancik,J.F., Riazuddin,S. (2008) Primary congenital glaucoma localizes to chromosome 14q24.2-24.3 in two consanguineous Pakistani families. Mol. Vis., 14, 1659-1665.
49. Waryah,A.M., Rehman,A., Ahmed,Z.M., Bashir,Z.H., Khan,S.Y., Zafar,A.U., Riazuddin,S., Friedman,T.B., Riazuddin,S. (2009) DFNB74, a novel autosomal recessive nonsyndromic hearing impairment locus on chromosome 12q14.2-q15. Clin. Genet., 76, 270-275.
50. Riazuddin,S., Anwar,S., Fischer,M., Ahmed,Z.M., Khan,S.Y., Janssen,A.G., Zafar,A.U., Scholl,U., Husnain,T., Belyantseva,I.A., et al. (2009) Molecular basis of DFNB73: mutations of BSND can cause nonsyndromic deafness or Bartter syndrome. Am. J. Hum. Genet., 85, 273-280.
51. Schultz,J.M., Khan,S.N., Ahmed,Z.M., Riazuddin,S., Waryah,A.M., Chhatre,D., Starost,M.F., Ploplis,B., Buckley,S., Velasquez,D., et al. (2009) Noncoding mutations of HGF are associated with nonsyndromic hearing loss, DFNB39. Am. J. Hum. Genet., 85, 25-39.
52. Anwar,S., Riazuddin,S., Ahmed,Z.M., Tasneem,S., Ateeq,u.J., Khan,S.Y., Griffith,A.J., Friedman,T.B., Riazuddin,S. (2009) SLC26A4 mutation spectrum associated with DFNB4 deafness and Pendred's syndrome in Pakistanis. J. Hum. Genet., 54, 266-270.
53. Choi,B.Y., Ahmed,Z.M., Riazuddin,S., Bhinder,M.A., Shahzad,M., Husnain,T., Riazuddin,S., Griffith,A.J., Friedman,T.B. (2009) Identities and frequencies of mutations of the otoferlin gene (OTOF) causing DFNB9 deafness in Pakistan. Clin. Genet., 75, 237-243.
54. Ahmed,Z.M., Riazuddin,S., Khan,S.N., Friedman,P.L., Riazuddin,S., Friedman,T.B. (2009) USH1H, a novel locus for type I Usher syndrome, maps to chromosome 15q22-23. Clin. Genet., 75, 86-91.
55. Ali,M., McKibbin,M., Booth,A., Parry,D.A., Jain,P., Riazuddin,S.A., Hejtmancik,J.F., Khan,S.N., Firasat,S., Shires,M., et al. (2009) Null mutations in LTBP2 cause primary congenital glaucoma. Am. J. Hum. Genet., 84, 664-671.
56. Hertzano,R., Puligilla,C., Chan,S.L., Timothy,C., Depireux,D.A., Ahmed,Z., Wolf,J., Eisenman,D.J., Friedman,T.B., Riazuddin,S., et al. (2010) CD44 is a Marker for the Outer Pillar Cells in the Early Postnatal Mouse Inner Ear. J. Assoc. Res. Otolaryngol..
57. Rehman,A.U., Morell,R.J., Belyantseva,I.A., Khan,S.Y., Boger,E.T., Shahzad,M., Ahmed,Z.M., Riazuddin,S., Khan,S.N., Riazuddin,S., Friedman,T.B. (2010) Targeted capture and next-generation sequencing identifies C9orf75, encoding taperin, as the mutated gene in nonsyndromic deafness DFNB79. Am. J. Hum. Genet., 86, 378-388.
58. Kang,C., Riazuddin,S., Mundorff,J., Krasnewich,D., Friedman,P., Mullikin,J.C., Drayna,D. (2010) Mutations in the lysosomal enzyme-targeting pathway and persistent stuttering. N. Engl. J. Med., 362, 677-685.
59. Odeh,H., Hunker,K.L., Belyantseva,I.A., Azaiez,H., Avenarius,M.R., Zheng,L., Peters,L.M., Gagnon,L.H., Hagiwara,N., Skynner,M.J., et al. (2010) Mutations in Grxcr1 are the basis for inner ear dysfunction in the pirouette mouse. Am. J. Hum. Genet., 86, 148-160.
60. Khan,S.Y., Riazuddin,S., Shahzad,M., Ahmed,N., Zafar,A.U., Rehman,A.U., Morell,R.J., Griffith,A.J., Ahmed,Z.M., Riazuddin,S., Friedman,T.B. (2010) DFNB79: reincarnation of a nonsyndromic deafness locus on chromosome 9q34.3. Eur. J. Hum. Genet., 18, 125-129.
61. Kaul,H., Riazuddin,S.A., Shahid,M., Kousar,S., Butt,N.H., Zafar,A.U., Khan,S.N., Husnain,T., Akram,J., Hejtmancik,J.F., Riazuddin,S. (2010) Autosomal recessive congenital cataract linked to EPHA2 in a consanguineous Pakistani family. Mol. Vis., 16, 511-517.
62. Naz,S., Riazuddin,S.A., Li,L., Shahid,M., Kousar,S., Sieving,P.A., Hejtmancik,J.F., Riazuddin,S. (2010) A Novel Locus for Autosomal Recessive Retinitis Pigmentosa in a Consanguineous Pakistani Family Maps to Chromosome 2p. Am. J. Ophthalmol..
63. Kaul,H., Riazuddin,S.A., Yasmeen,A., Mohsin,S., Khan,M., Nasir,I.A., Khan,S.N., Husnain,T., Akram,J., Hejtmancik,J.F., Riazuddin,S. (2010) A new locus for autosomal recessive congenital cataract identified in a Pakistani family. Mol. Vis., 16, 240-245.
64. Yasmeen,A., Riazuddin,S.A., Kaul,H., Mohsin,S., Khan,M., Qazi,Z.A., Nasir,I.A., Zafar,A.U., Khan,S.N., Husnain,T., et al. (2010) Autosomal recessive congenital cataract in consanguineous Pakistani families is associated with mutations in GALK1. Mol. Vis., 16, 682-688.
65. Kaul H, Riazuddin SA, Yasmeen A, Mohsin S, Khan M, et al. (2010) A new locus for autosomal recessive congenital cataract identified in a Pakistani family. Molecular Vison 16: 240-245.
66. Naz S, Riazuddin SA, Li L, Shahid M, Kousar S, et al. (2010) A Novel Locus for Autosomal Recessive Retinitis Pigmentosa in a Consanguineous Pakistani Family Maps to Chromosome 2p. AmJOphthalmol 149: 861-866.
67. Kaul H, Riazuddin SA, Shahid M, Kousar S, Butt NH, et al. (2010) Autosomal recessive congenital cataract linked to EPHA2 in a consanguineous Pakistani family. Molecular Vison 16: 511-517.
68. Yasmeen A, Riazuddin SA, Kaul H, Mohsin S, Khan M, et al. (2010) Autosomal recessive congenital cataract in consanguineous Pakistani families is associated with mutations in GALK1. Molecular Vison 16: 682-688.
69. Riazuddin SA, Shahzadi A, Zeitz C, Ahmed ZM, Ayyagari R, et al. (2010) A mutation in SLC24A1 implicated in autosomal-recessive congenital stationary night blindness. American Journal of Human Genetics 87: 523-531.
70. Kaul H, Riazuddin SA, Qazi ZA, Nasir IA, Zafar AU, et al. (2010) Ectopia lentis in a consanguineous pakistani family and a novel locus on chromosome 8q. Arch Ophthalmol 128: 1046-1049.
71. Shahzadi A, Riazuddin SA, Ali S, Li D, Khan SN, et al. (2010) Nonsense mutation in MERTK causes autosomal recessive retinitis pigmentosa in a consanguineous Pakistani family. BrJOphthalmol 94: 1094-1099.
72. Riazuddin SA, Iqbal M, Wang Y, Masuda T, Chen Y, et al. (2010) A splice-site mutation in a retina-specific exon of BBS8 causes nonsyndromic retinitis pigmentosa. American Journal of Human Genetics 86: 805-812.
73. Li L, Nakaya N, Chavali VR, Ma Z, Jiao X, et al. (2010) A mutation in ZNF513, a putative regulator of photoreceptor development, causes autosomal-recessive retinitis pigmentosa. American Journal of Human Genetics 87: 400-409.
74. Sabir N, Riazuddin SA, Butt T, Iqbal F, Nasir IA, et al. (2010) Mapping of a new locus associated with autosomal recessive congenital cataract to chromosome 3q. Molecular Vison 16: 2634-2638.
75. Sabir N, Riazuddin SA, Kaul H, Iqbal F, Nasir IA, et al. (2010) Mapping of a novel locus associated with autosomal recessive congenital cataract to chromosome 8p. Molecular Vison 16: 2911-2915.
76. Naz S, Ali S, Riazuddin SA, Farooq T, Butt NH, et al. (2011) Mutations in RLBP1 associated with fundus albipunctatus in consanguineous Pakistani families. Br J Ophthalmol 95: 1019-1024.
77. Chen J, Smaoui N, Hammer M, Jiao X, Riazuddin SA, et al. (2011) Molecular analysisof Bardet-Biedl syndrome families:report of 21 novel mutations in 10 genes. Invest Ophthalmol Vis Sci 52: 5317-5324.
78. Chen J, Ma Z, Jiao X, Fariss R, Kantorow WL, et al. (2011) Mutations in FYCO1 Cause Autosomal-Recessive Congenital Cataracts. Am J Hum Genet.
79. Ali S, Riazuddin SA, Shahzadi A, Nasir IA, Khan SN, et al. (2011) Mutations in the beta-subunit of rod phosphodiesterase identified in consanguineous Pakistani families with autosomal recessive retinitis pigmentosa. Mol Vis 17: 1373-1380.
80. Iqbal M, Naeem MA, Riazuddin SA, Ali S, Farooq T, et al. (2011) Association of Pathogenic Mutations in TULP1 With Retinitis Pigmentosa in Consanguineous Pakistani Families. Arch Ophthalmol 129: 1351-1357.
81. Naeem MA, Chavali VR, Ali S, Iqbal M, Riazuddin S, et al. (2012) GNAT1 Associated with Autosomal Recessive Congenital Stationary Night Blindness. Invest Ophthalmol Vis Sci 53: 1353-1361.

82. Kabir F., Naz S., Riazuddin S.A., Naeem M.A., Khan S.N., Husnain T., Akram J., Sieving P.A., Hejtmancik J.F., Riazuddin S. Novel mutations in RPE65 identified in consanguineous Pakistani families with retinal dystrophy. Mol Vis 2013:19:1554-1564.

83. Ali S., Khan S.Y., Naeem M.A., Khan S.N., Husnain T., Riazuddin S., Ayyagari R., Riazuddin S., Hejtmancik J.F., Riazuddin S.A. Phenotypic Variability Associated with the D226N Allele of IMPDH1. Ophthalmology 2014:122:429-431.

84. Li D., Jin C., Jiao X., Li L., Bushra T., Naeem M.A., Butt N.H., Husnain T., Sieving P.A., Riazuddin S., Riazuddin S.A., Hejtmancik J.F. AIPL1 implicated in the pathogenesis of two cases of autosomal recessive retinal degeneration. Mol Vis 2014:20:1-xx.

85. Maranhao B., Biswas P., Duncan J.L., Branham K.E., Silva G.A., Naeem M.A., Khan S.N., Riazuddin S., Hejtmancik J.F., Heckenlively J.R., Riazuddin S.A., Lee P.L., Ayyagari R. exomeSuite: Whole exome sequence variant filtering tool for rapid identification of putative disease causing SNVs/indels. Genomics 2014:103:169-176.

86. Chassine T., Bocquet B., Daien V., Avila-Fernandez A., Ayuso C., Collin R.W., Corton M., Hejtmancik J.F., van den Born L.I., Klevering B.J., Riazuddin S.A., Sendon N., Lacroux A., Meunier I., Hamel C.P. Autosomal recessive retinitis pigmentosa with RP1 mutations is associated with myopia. Br J Ophthalmol 2015.

87. Hejtmancik J.F., Riazuddin S.A., McGreal R., Liu W., Cvekl A., Shiels A. Lens Biology and Biochemistry. Progress in molecular biology and translational science 2015:134:169-201.

88. Jiaox X., Khan S.Y., Irum B., Khan A.O., Wang Q., Kabir F., Khan A.A., Husnain T., Akram J., Riazuddin S., Hejtmancik J.F., Riazuddin S.A. Missense Mutations in CRYAB Are Liable for Recessive Congenital Cataracts. PLoS One 2015:10:e0137973.

89. Khan S.Y., Ali S., Naeem M.A., Khan S.N., Husnain T., Butt N.H., Qazi Z.A., Akram J., Riazuddin S., Ayyagari R., Hejtmancik J.F., Riazuddin S.A. Splice-site mutations identified in PDE6A responsible for retinitis pigmentosa in consanguineous Pakistani families. Mol Vis 2015:21:871-882.

90. Maranhao B., Biswas P., Gottsch A.D., Navani M., Naeem M.A., Suk J., Chu J., Khan S.N., Poleman R., Akram J., Riazuddin S., Lee P., Riazuddin S.A., Hejtmancik J.F., Ayyagari R. Investigating the Molecular Basis of Retinal Degeneration in a Familial Cohort of Pakistani Decent by Exome Sequencing. PLoS One 2015:10:e0136561.

91. Naeem M.A., Gottsch A.D., Ullah I., Khan S.N., Husnain T., Butt N.H., Qazi Z.A., Akram J., Riazuddin S., Ayyagari R., Hejtmancik J.F., Riazuddin S.A. Mutations in GRM6 identified in consanguineous Pakistani families with congenital stationary night blindness. Mol Vis 2015:21:1261-1271.

92. Biswas P., Chavali V.R., Agnello G., Stone E., Chakarova C., Duncan J.L., Kannabiran C., Homsher M., Bhattacharya S.S., Naeem M.A., Kimchi A., Sharon D., Iwata T., Riazuddin S., Reddy G.B., Hejtmancik J.F., Georgiou G., Riazuddin S.A., Ayyagari R. A missense mutation in ASRGL1 is involved in causing autosomal recessive retinal degeneration. Hum Mol Genet 2016.

93. Jiao X., Kabir F., Irum B., Khan A.O., Wang Q., Li D., Khan A.A., Husnain T., Akram J., Riazuddin S., Hejtmancik J.F., Riazuddin S.A. A Common Ancestral Mutation in CRYBB3 Identified in Multiple Consanguineous Families with Congenital Cataracts. PLoS One 2016:11:e0157005.

94. Kabir F., Ullah I., Ali S., Gottsch A.D., Naeem M.A., Assir M.Z., Khan S.N., Akram J., Riazuddin S., Ayyagari R., Hejtmancik J.F., Riazuddin S.A. Loss of function mutations in RP1 are responsible for retinitis pigmentosa in consanguineous familial cases. Mol Vis 2016:22:610-625.

95. Khan S.Y., Vasanth S., Kabir F., Gottsch J.D., Khan A.O., Chaerkady R., Lee M.C., Leitch C.C., Ma Z., Laux J., Villasmil R., Khan S.N., Riazuddin S., Akram J., Cole R.N., Talbot C.C., Pourmand N., Zaghloul N.A., Hejtmancik J.F., Riazuddin S.A. FOXE3 contributes to Peters anomaly through transcriptional regulation of an autophagy-associated protein termed DNAJB1. Nature communications 2016:7:10953.

96. Ullah I., Kabir F., Iqbal M., Gottsch C.B., Naeem M.A., Assir M.Z., Khan S.N., Akram J., Riazuddin S., Ayyagari R., Hejtmancik J.F., Riazuddin S.A. Pathogenic mutations in TULP1 responsible for retinitis pigmentosa identified in consanguineous familial cases. Mol Vis 2016:22:797-815.

97. Biswas P., Duncan J.L., Ali M., Matsui H., Naeem M.A., Raghavendra P.B., Frazer K.A., Arts H.H., Riazuddin S., Akram J., Hejtmancik J.F., Riazuddin S.A., Ayyagari R. A mutation in IFT43 causes non-syndromic recessive retinal degeneration. Hum Mol Genet 2017.

98. Chen J., Wang Q., Cabrera P.E., Zhong Z., Sun W., Jiao X., Chen Y., Govindarajan G., Naeem M.A., Khan S.N., Ali M.H., Assir M.Z., Rahman F.U., Qazi Z.A., Riazuddin S., Akram J., Riazuddin S.A., Hejtmancik J.F. Molecular Genetic Analysis of Pakistani Families With Autosomal Recessive Congenital Cataracts by Homozygosity Screening. Invest Ophthalmol Vis Sci 2017:58:2207-2217.

99. Li L., Chen Y., Jiao X., Jin C., Jiang D., Tanwar M., Ma Z., Huang L., Ma X., Sun W., Chen J., Ma Y., M'Hamdi O., Govindarajan G., Cabrera P.E., Li J., Gupta N., Naeem M.A., Khan S.N., Riazuddin S., Akram J., Ayyagari R., Sieving P.A., Riazuddin S.A., Hejtmancik J.F. Homozygosity Mapping and Genetic Analysis of Autosomal Recessive Retinal Dystrophies in 144 Consanguineous Pakistani Families. Invest Ophthalmol Vis Sci 2017:58:2218-2238.

Appendix II: Families with Retinitis pigmentosa will be screened for these known loci:

Locus
Location ABI Panel to be used for Screening

ABCA4, ABCR, RP19, STGD1; 1p21-p22 1 & 2
248200, 601691, 601718
RPE65, LCA2, RP20; 1p31 1 & 2
180069, 204100
CRB1, RP12; 1q31-q32.1 1 & 2
600105, 604210, 268030
RP28 2p11-p16 3 & 4
RP26 2q31-q33 3 & 4
SAG; 2q37.1 3 & 4
181031, 258100
RHO, RP4; 3q21-q24 5, 6 & 7
180380
CNGA1, CNCG, CNCG1; 4p12-cen 5, 6 & 7
123825
RP29 4q32-q34 5, 6 & 7
LRAT; 4q31.2 5, 6 & 7
604863
PDE6B, CSNB3; 4p16.3 5, 6 & 7
163500, 180072
PDE6A; 5q31.2-q34 8, 9 & 10
180071
RP25; 6cen-q15 8, 9 & 10
602772
TULP1, RP14; 6p21.3 8, 9 & 10
600132, 602280
TTPA; 8q13.1-q13.3 11 & 12
600415
RGR; 10q23 13, 14, 15 & 16
600342
RBP4; 10q24 13, 14, 15 & 16
180250
NR2E3, ESCS, PNR; 15q23 21 & 22
268100, 604485
RLBP1, CRALBP; 15q26 21 & 22
180090
RP22; 16p12.1-p12.3 21 & 22
602594
CNGB1, CNCG2, CNCG3L, GAR1, GARP; 16q13-q21 21 & 22
600724

Appendix III: Families with hereditary cataracts will be screened for these known loci:

Locus Chromosome Inheritance Candidate
Rh linked 1p36 AD
CCV (Volkmann) 1p36 AD
CTPP (Posterior Polar) 1p34-p36 AD
CAE1 (CZP1,Duffy-linked) 1q21-q25 AD connexin 50* (GJA8, near Duffy locus), E48K, P88S
CCL (Coppock-like)/variable nuclear and nuclear lamellar 2q33-q35 AD GammaC-crystallin*, TSP, G41ins
CACA 2q33-35 AD gammaD-crystallin*, R14C, R37S, R58H
3p22-p24.2 AR
BFSP2 3q21-q22 AD BFSP2* (CP49, phakinen) DE233 and R287W
i blood group 6 AR
ARCC? 9q13-q22 AR
CRYAB 11q23.3-24.2 AD alphaB-crystallin 450delA
ADC(Bronwyn) 12q12-14.1 AD MIP (AQP0), E134G, T138R, delG213
CZP3 13q11-13 AD connexin 46 (GJA3)*, N63S, insC380, P187L
ADCC? 15q21-q22 AD
CTM (CAM) (Marner), CCDN 16q22.1,near haptoglobin AD
CTAA2 (Anterior Polar) 17p13 AD
CCZS (Zonular Sutural) 17q11-q12 AD betaA3-crystallin* X20/X37 (G->C, G->A)
CCA1 (Cerulean - blue dot) 17q24 AD
CPP3 20p12-q12 AD
CRYAA,ARG116CYS 21q22.3 AD, AR alphaA-crystallin*, R116C (C->T), W9X (G->A), R49C (C->T)
CCA2 (Cerulean - blue dot) 22q11.2 AD betaB2-crystallin* (in beta-crystallin cluster), Q155X (both)
CRYBB1 22q11.2 AD betaB1-crystallin G220X (G->T)
CCT Xp22 XL
Complex Cataract Syndromes
FOXE3 1p32 AD FOXE3
ASD 8q13.3 AD EYA1
spastic paraplegia with cataracts 10q23.3-24.2
PITX3 10q25 PITX3*
CRYAB,R120G 11q22.3-33.1 alpha-crystallin*, R129G
Hyperferritinemia-cataract syndrome 19q13.4 AD ferritin
Appendix III: Families with hereditary cataracts will be screened for these known loci:

References
1. Chen, J., Wang, Q., Cabrera, P.E., Zhong, Z., Sun, W., Jiao, X., Chen, Y., Govindarajan, G., Naeem, M.A., Khan, S.N., et al. (2017). Molecular Genetic Analysis of Pakistani Families With Autosomal Recessive Congenital Cataracts by Homozygosity Screening. Invest Ophthalmol Vis Sci 58, 2207-2217.
2. Li, L., Chen, Y., Jiao, X., Jin, C., Jiang, D., Tanwar, M., Ma, Z., Huang, L., Ma, X., Sun, W., et al. (2017). Homozygosity Mapping and Genetic Analysis of Autosomal Recessive Retinal Dystrophies in 144 Consanguineous Pakistani Families. Invest Ophthalmol Vis Sci 58, 2218-2238.
3. Devi, R.R., Yao, W., Vijayalakshmi, P., Sergeev, Y.V., Sundaresan, P., and Hejtmancik, J.F. (2008). Crystallin gene mutations in Indian families with inherited pediatric cataract. Mol Vis 14, 1157-1170.

 

Added: Mar 23, 2018 7:21 pm This is a combined synopsis/solicitation for commercial items prepared in accordance with the format in Subpart 12.6 and FAR Part 13, Simplified Acquisitions Procedures. This announcement constitutes the only solicitation; quotations are not being requested and a written solicitation will not be issued. This is a Notice of Intent. The announcement number for this acquisition is NIH-OLAO-OD3-NOI8669018 and is being issued under the authority of FAR Subpart 6.302-1, 10 U.S.C. 2304(c)(1). Only one responsible source and no other supplies or services will satisfy agency requirements. The anticipated award date April 1, 2018. The incorporated provisions and clauses are those in effect through Federal Acquisition Circular 2005-58 dated May 18, 2012. This acquisition will be processed under Simplified Acquisition Procedures (SAP) and is not a small business set-aside. The associated North American Industry Classification System (NAICS) Code is 621511, which has a size standard of $13.5 million.
The National Institutes of Health, Office of the Director, Office of Logistics and Acquisitions Operations, on the behalf of the National Institutes Eye Institute's Intramural Research Program, intends to procure on a sole source basis from Allama Iqbal Medical Research Centre, to support the expanding NEI Intramural Clinical Research Program which will include the following tasks:

The contractor will be responsible for:
•a. Ascertainment of families with a history of recessive retinitis pigmentosa or hereditary cataracts.
•b. The conduct of on-site assessments of families with a history of recessive retinitis pigmentosa or cataracts. The contractor will screen all available family members to identify affected and unaffected individuals, and will take detailed medical histories, from which family pedigrees will be developed.
•c. Performing or supervising ophthalmic examinations from these individuals. These examinations will include one or more of the following:
•a. Visual function testing
•b. Perimetry
•c. Fundoscopic examination
•d. Electroretinography
•e. Humphries peripheral field examination
•f. Other tests as mutually agreed upon by the NEI and contractor
•d. Collecting blood samples for DNA isolation/transformation and analysis at the NEI and optionally at the National Centre of Excellence in Molecular Biology at the University of the Punjab
•e. Shipment of non-hemolyzed blood samples or DNA samples to the NEI by Federal Express or other comparable express mail service.
•a. Preservation, packaging, and packing shall be used to afford adequate protection against corrosion, deterioration, and physical damage during shipment. The NEI will provide packaging if requested.
•b. Standard commercial marking shall be used for shipping, with each container labeled with the contractors name and address and the total number of samples in the shipment.
•c. Each blood sample shall be labeled with the individuals name, date of birth, and the date the sample was drawn
•d. Each DNA sample, 100 micrograms of DNA in TE, should be labeled with an arbitrary laboratory identifier, and information as in 3) should be included in accompanying paperwork for that identifier.
•e. Blood samples from one affected individual in each family should arrive at the NEI within 3 days after blood drawing.
•f. At the time of blood drawing, a small amount of blood should be spotted on a Guthrie card, which should be sent with the blood or DNA.

This is a fixed-price contract and the FOB term is Origin and Payment Net 30 days. FAR provisions and clauses that apply to this acquisition: FAR 52.212-1, Instructions to Offerors, Commercial Items; FAR 52.212-2 Evaluation-Commercial Items; FAR 52.212-3, Offeror Representations and Certifications-Commercial Items; Far 52.212-4 Contract Terms and Conditions Commercial Items; FAR 52.212-5, Contract Terms and Conditions Required to Implement Statutes or Executive Orders, Commercial Items; and FAR 52.225-1, Buy American Act-Supplies; FAR 52.204-7, Central Contractor Registration; and FAR 32.703-2, Availability of Funds, FAR 52.232-34, Payment by Electronic Funds Transfer-Other than Central Contractor Registration. In order to be considered for an award, an offeror must have completed the online electronic Representations and Certifications located at http://orca.bpn.gov/ in accordance with FAR 4.1201(a). By submission of an offer, the offeror acknowledges the requirement that a prospective awardee shall be registered in the CCR at www.ccr.gov prior to award during performance, and through final payment of any contract, basic agreement, basic ordering agreement, or blanket purchasing agreement resulting from this solicitation. [Note: Lack of registration in the Central Contractor Registration will make an offeror ineligible for award].

This notice of intent is not a request for competitive quotations; however, the Government will consider responses submitted. Responses must be submitted no later than 3:00 PM Eastern Standard Time (EST), March 28, 2018 to Ms. Anita Edwards via e-mail to ae22u@nih.gov. Electronic submission ONLY will be accepted. All information furnished must contain sufficient detail to allow the government to determine if it can meet the above specifications described herein. A determination by the Government not to compete the proposed acquisition based upon responses to this notice is solely within the discretion of the Government. Information received will normally be considered solely for the purpose of determining whether to conduct a competitive procurement. Please reference the announcement number NIH-OLAO-OD3-NOI8669018 on all correspondence.

Requests for information concerning this requirement must be submitted in writing can be E-mailed to ae22u@nih.gov. It is the vendor's responsibility to confirm receipt of all quotations and/or questions by the closing date of this announcement via e-mail. Calls will not be accepted.