期刊
NATURE COMMUNICATIONS
卷 11, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-17452-6
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资金
- International Research Support Initiative Program fellowship from the Higher Education Commission of Pakistan
- U.S. National Human Genome Research Institute (NHGRI) [T32HG008955]
- National Institute of General Medical Sciences (NIGMS) [R01GM093937]
- Cancer Research UK [C309/A25144]
- Korean Ministry of Trade, Industry and Energy [10063396]
- National Research Foundation (NRF) of Korea [2018M3A9B8021980]
- National Institute of Mental Health (NIMH) [R01MH106826]
- National Institute of Neurological Disorders and Storke (NINDS) [R01NS073854]
- South Carolina Department of Disabilities and Special Needs (SCDDSN) [2015-45]
- Korea Evaluation Institute of Industrial Technology (KEIT) [10063396] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Intellectual disability (ID) is a heterogeneous clinical entity and includes an excess of males who harbor variants on the X-chromosome (XLID). We report rare FAM50A missense variants in the original Armfield XLID syndrome family localized in Xq28 and four additional unrelated males with overlapping features. Our fam50a knockout (KO) zebrafish model exhibits abnormal neurogenesis and craniofacial patterning, and in vivo complementation assays indicate that the patient-derived variants are hypomorphic. RNA sequencing analysis from fam50a KO zebrafish show dysregulation of the transcriptome, with augmented spliceosome mRNAs and depletion of transcripts involved in neurodevelopment. Zebrafish RNA-seq datasets show a preponderance of 3' alternative splicing events in fam50a KO, suggesting a role in the spliceosome C complex. These data are supported with transcriptomic signatures from cell lines derived from affected individuals and FAM50A protein-protein interaction data. In sum, Armfield XLID syndrome is a spliceosomopathy associated with aberrant mRNA processing during development.
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