Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content.
Hum Mol Genet
; 29(9): 1426-1439, 2020 06 03.
Article
em En
| MEDLINE
| ID: mdl-32202298
ABSTRACT
Defects in the mRNA export scaffold protein GANP, encoded by the MCM3AP gene, cause autosomal recessive early-onset peripheral neuropathy with or without intellectual disability. We extend here the phenotypic range associated with MCM3AP variants, by describing a severely hypotonic child and a sibling pair with a progressive encephalopathic syndrome. In addition, our analysis of skin fibroblasts from affected individuals from seven unrelated families indicates that disease variants result in depletion of GANP except when they alter critical residues in the Sac3 mRNA binding domain. GANP depletion was associated with more severe phenotypes compared with the Sac3 variants. Patient fibroblasts showed transcriptome alterations that suggested intron content-dependent regulation of gene expression. For example, all differentially expressed intronless genes were downregulated, including ATXN7L3B, which couples mRNA export to transcription activation by association with the TREX-2 and SAGA complexes. Our results provide insight into the molecular basis behind genotype-phenotype correlations in MCM3AP-associated disease and suggest mechanisms by which GANP defects might alter RNA metabolism.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acetiltransferases
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Fatores de Transcrição
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Proteínas Nucleares
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Monoéster Fosfórico Hidrolases
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Peptídeos e Proteínas de Sinalização Intracelular
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Flavoproteínas
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Doenças do Sistema Nervoso
Limite:
Child
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Child, preschool
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article