Bi-allelic missense variant, p.Ser35Leu in EXOSC1 is associated with pontocerebellar hypoplasia.
Alleles
Amino Acid Sequence
Amino Acid Substitution
Brain
/ pathology
Cerebellar Diseases
/ genetics
Consanguinity
Developmental Disabilities
/ genetics
Exosome Multienzyme Ribonuclease Complex
/ genetics
Humans
Infant
Male
Mutation, Missense
Pedigree
Protein Conformation
RNA-Binding Proteins
/ genetics
Sequence Alignment
Sequence Homology, Amino Acid
Exome Sequencing
EXOSC1
RNA exosome
blue native PAGE
pontocerebellar hypoplasia
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
04 2021
04 2021
Historique:
received:
24
10
2020
revised:
21
12
2020
accepted:
14
01
2021
pubmed:
20
1
2021
medline:
21
1
2022
entrez:
19
1
2021
Statut:
ppublish
Résumé
RNA exosome is a highly conserved ribonuclease complex essential for RNA processing and degradation. Bi-allelic variants in exosome subunits EXOSC3, EXOSC8 and EXOSC9 have been reported to cause pontocerebellar hypoplasia type 1B, type 1C and type 1D, respectively, while those in EXOSC2 cause short stature, hearing loss, retinitis pigmentosa and distinctive facies. We ascertained an 8-months-old male with developmental delay, microcephaly, subtle dysmorphism and hypotonia. Pontocerebellar hypoplasia and delayed myelination were noted on neuroimaging. A similarly affected elder sibling succumbed at the age of 4-years 6-months. Chromosomal microarray returned normal results. Exome sequencing revealed a homozygous missense variant, c.104C > T p.(Ser35Leu) in EXOSC1 (NM_016046.5) as the possible candidate. In silico mutagenesis revealed loss of a polar contact with neighboring Leu37 residue. Quantitative real-time PCR indicated no appreciable differences in EXOSC1 transcript levels. Immunoblotting and blue native PAGE revealed reduction in the EXOSC1 protein levels and EXO9 complex in the proband, respectively. We herein report an individual with the bi-allelic variant c.104C>T p.(Ser35Leu) in EXOSC1 and clinical features of pontocerebellar hypoplasia type 1. Immunoblotting and blue native PAGE provide evidence for the pathogenicity of the variant. Thus, we propose EXOSC1 as a novel candidate gene for pontocerebellar hypoplasia.
Identifiants
pubmed: 33463720
doi: 10.1111/cge.13928
pmc: PMC9990822
mid: NIHMS1875609
doi:
Substances chimiques
EXOSC1 protein, human
0
RNA-Binding Proteins
0
Exosome Multienzyme Ribonuclease Complex
EC 3.1.-
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
594-600Subventions
Organisme : NICHD NIH HHS
ID : R01 HD093570
Pays : United States
Informations de copyright
© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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