DE novo mutations in replication-independent histone genes and an unexplored class of rare pediatric mendelian syndromes
Ended Project Grant Awarded Last action
- Award ID
- F30HD112125
- Recipient
-
The Trustees Of The University Of Pennsylvania UEI GM1XX56LEP58
- Awarding agency
-
National Institute of Child Health and Human Development
National Institutes of Health, Department of Health and Human Services
- Obligated
- $389,722
Award facts
- Assistance listing
- 93.865 Child Health and Human Development Extramural Research
- Completion date
- Place of performance
- Philadelphia, PA 19104, USA
Award details come from USAspending.gov.
Description
- Abstract
- Heterozygous germline missense mutations in replication-independent (RI) histones are emerging as the cause of histonopathies, a devastating class of pediatric neurodevelopmental disorders (ndds). However, the neurobiological function of histones in human pathology and, more broadly, in development is understudied. In part, this is due to the high degree of homology shared by the ~100 histone encoding-genes, which has historically rendered them refractory to genetic sequencing. This proposed work builds on our innovative histone variation intolerance prediction project that we pursued to overcome traditional histone-specific limitations. In my 2022 publication of this work, we more than doubled the list of RI-histonopathy disease genes from 3 to 8. We have since built unpublished cohorts of patients for 4 of the 5 novel disease genes, including an unrelated cohort who share a pathogenic DE novo heterozygous germline missense mutation in MACROH2A1 (c.80G>a, p.R27Q). Our patients' phenotypes exhibit substantial overlap with those of patients harboring heterozygous missense mutations in other RI histones, suggesting a shared pathogenic mechanism. We hypothesize that this MACROH2A1 DE novo heterozygous germline missense mutation causes an NDD through a gain-of-function mechanism that results in destabilization of the nucleosome and transcriptional DE-repression. In aim 1, we will interrogate fundamental features of MACROH2A1 in a human model of neurodevelopment, which enables US to probe human-specific processes that cannot be modeled in other systems. Further, the phenotypic overlap between our patients and those with other RI-histonopathies suggests that studying how the recurrent MACROH2A1 mutation perturbs human neurodevelopment will provide key insights into other histonopathies. Thus, in aim 2, we will quantify the epigenetic dysregulation caused by our patients' mutation. This work will be performed in the extensively characterized KOLF2.1J-background hipsc line. We are employing a multifaceted approach involving analysis of publicly available transcriptomic data, RT-qpcr, quantitative mass spectrometry, chip-SEQ, cut & run, cytosine base editing, bulk RNA-SEQ, EDU incorporation assays, facs analysis, nuclear CO-immunoprecipitation and atac-SEQ to complete these aims. Our results will advance the field of developmental histone biology and have great translational impact, including establishing a foundation for therapeutic development for the histonopathy patient population that currently only receives palliative measures. The proposed work will be carried out in the world-class training environment cultivated between the university of pennsylvania and the children's hospital of philadelphia, within the bhoj lab, which has a history of making profound advances in the histone biology field. Additionally, the guidance from an exceptional sponsorship team of DRS. Bhoj and hakonarson, in conjunction with collaborators who are pioneers in their fields, will enable the successful completion of this fellowship proposal and the development of a competent, independent investigator capable of producing rigorous and reproducible patient-driven work.
Transactions
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| Amendment | -$27,824 | |
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| Amendment | $52,694 | |
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| Amendment | $52,694 | |
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| Original award | $0 |
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Quick answers
Who received award F30HD112125?
F30HD112125 was awarded to The Trustees Of The University Of Pennsylvania by National Institute of Child Health and Human Development (National Institutes of Health) on August 23, 2024.
How much is award F30HD112125 worth?
$389,722 has been obligated on F30HD112125.
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