PUBLICATION

Mutations in FAM50A suggest that Armfield XLID syndrome is a spliceosomopathy

Authors
Lee, Y.R., Khan, K., Armfield-Uhas, K., Srikanth, S., Thompson, N.A., Pardo, M., Yu, L., Norris, J.W., Peng, Y., Gripp, K.W., Aleck, K.A., Li, C., Spence, E., Choi, T.I., Kwon, S.J., Park, H.M., Yu, D., Do Heo, W., Mooney, M.R., Baig, S.M., Wentzensen, I.M., Telegrafi, A., McWalter, K., Moreland, T., Roadhouse, C., Ramsey, K., Lyons, M.J., Skinner, C., Alexov, E., Katsanis, N., Stevenson, R.E., Choudhary, J.S., Adams, D.J., Kim, C.H., Davis, E.E., Schwartz, C.E.
ID
ZDB-PUB-200728-5
Date
2020
Source
Nature communications   11: 3698 (Journal)
Registered Authors
Davis, Erica, Katsanis, Nicholas, Kim, Cheol-Hee
Keywords
none
Datasets
GEO:GSE145711
MeSH Terms
  • RNA Splicing/genetics
  • Intellectual Disability/genetics*
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
  • X-Linked Intellectual Disability/genetics*
  • Cell Nucleus/metabolism
  • Child, Preschool
  • Mice
  • DNA-Binding Proteins/genetics*
  • Gene Expression Regulation, Developmental
  • Mutation, Missense/genetics
  • Adult
  • Mutation/genetics*
  • Humans
  • Protein Transport
  • Female
  • NIH 3T3 Cells
  • Pedigree
  • Phenotype
  • Male
  • Syndrome
  • Animals
  • Spliceosomes/metabolism*
  • Family
  • Zebrafish/genetics
  • Child
  • RNA, Small Nuclear/genetics
  • RNA-Binding Proteins/genetics*
(all 30)
PubMed
32703943 Full text @ Nat. Commun.
Abstract
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.
Genes / Markers
Figures
Figure Gallery (6 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ck125a
    Complex
    ck125b
      Small Deletion
      knu3TgTransgenic Insertion
        s843TgTransgenic Insertion
          zdf1
            Point Mutation
            zf195TgTransgenic Insertion
              1 - 6 of 6
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              Human Disease / Model
              No data available
              Sequence Targeting Reagents
              Target Reagent Reagent Type
              fam50aCRISPR1-fam50aCRISPR
              fam50aCRISPR2-fam50aCRISPR
              fam50aMO1-fam50aMRPHLNO
              1 - 3 of 3
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              Fish
              Antibodies
              Name Type Antigen Genes Isotypes Host Organism
              Ab1-fam50apolyclonal
                IgGRabbit
                Ab17-gapdhmonoclonal
                  IgG1Mouse
                  1 - 2 of 2
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                  Orthology
                  No data available
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  EGFPEFGEGFP
                  1 - 1 of 1
                  Show
                  Mapping
                  No data available