Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content.
Acetyltransferases
/ chemistry
Age of Onset
Antigens, Surface
/ genetics
Cell Nucleus
/ genetics
Child
Child, Preschool
Exodeoxyribonucleases
/ genetics
Female
Flavoproteins
/ genetics
Gene Expression Regulation
/ genetics
Glycoproteins
/ genetics
Humans
Intellectual Disability
/ genetics
Intracellular Signaling Peptides and Proteins
/ chemistry
Introns
/ genetics
Male
Nervous System Diseases
/ genetics
Nuclear Proteins
/ genetics
Peripheral Nervous System Diseases
/ genetics
Phenotype
Phosphoproteins
/ genetics
Phosphoric Monoester Hydrolases
/ genetics
Protein Conformation
RNA Transport
/ genetics
RNA, Messenger
/ genetics
Transcription Factors
/ genetics
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
03 06 2020
03 06 2020
Historique:
received:
29
01
2020
revised:
17
03
2020
accepted:
19
03
2020
pubmed:
24
3
2020
medline:
13
8
2021
entrez:
24
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32202298
pii: 5810984
doi: 10.1093/hmg/ddaa051
pmc: PMC7297229
mid: EMS86591
doi:
Substances chimiques
ATXN7L3B protein, human
0
Antigens, Surface
0
Flavoproteins
0
Glycoproteins
0
Intracellular Signaling Peptides and Proteins
0
Nuclear Proteins
0
PCID2 protein, human
0
Phosphoproteins
0
RNA, Messenger
0
SAGA-1 protein, human
0
Transcription Factors
0
Acetyltransferases
EC 2.3.1.-
MCM3AP protein, human
EC 2.3.1.-
Exodeoxyribonucleases
EC 3.1.-
TREX2 protein, human
EC 3.1.16.-
FIG4 protein, human
EC 3.1.3.-
Phosphoric Monoester Hydrolases
EC 3.1.3.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1426-1439Subventions
Organisme : Medical Research Council
ID : MC_U105178939
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/K010611/1
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007748
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press.
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