Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy.
View/ Open
Date
2020-07-23Author
Lee, Y-R
Khan, K
Armfield-Uhas, K
Srikanth, S
Thompson, NA
Pardo, M
Yu, L
Norris, JW
Peng, Y
Gripp, KW
Aleck, KA
Li, C
Spence, E
Choi, T-I
Kwon, SJ
Park, H-M
Yu, D
Heo, WD
Mooney, MR
Baig, SM
Wentzensen, IM
Telegrafi, A
McWalter, K
Moreland, T
Roadhouse, C
Ramsey, K
Lyons, MJ
Skinner, C
Alexov, E
Katsanis, N
Stevenson, RE
Choudhary, JS
Adams, DJ
Kim, C-H
Davis, EE
Schwartz, CE
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Subject
NIH 3T3 Cells
Cell Nucleus
Spliceosomes
Animals
Zebrafish
Humans
Mice
Mental Retardation, X-Linked
Syndrome
RNA-Binding Proteins
DNA-Binding Proteins
Zebrafish Proteins
RNA, Messenger
RNA, Small Nuclear
Pedigree
Family
Gene Expression Regulation, Developmental
RNA Splicing
Protein Transport
Phenotype
Mutation
Mutation, Missense
Adult
Child
Child, Preschool
Female
Male
Intellectual Disability
Research team
Functional Proteomics Group
Language
eng
Date accepted
2020-06-17
License start date
2020-07-23
Citation
Nature communications, 2020, 11 (1), pp. 3698 - ?
Publisher
NATURE PORTFOLIO