Digenic inheritance of STUB1 variants and TBP polyglutamine expansions explains the incomplete penetrance of SCA17 and SCA48.
CHIP
Digenic disease
Huntington disease-like phenotype
Polyglutamine
Spinocerebellar ataxia
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
received:
04
05
2021
revised:
04
05
2021
accepted:
10
08
2021
pubmed:
16
12
2021
medline:
23
3
2022
entrez:
15
12
2021
Statut:
ppublish
Résumé
This study aimed to unravel the genetic factors underlying missing heritability in spinocerebellar ataxia type 17 (SCA17) caused by polyglutamine-encoding CAG/CAA repeat expansions in the TBP gene. Alleles with >49 CAG/CAA repeats are fully penetrant. Most patients, however, carry intermediate TBP Using next-generation sequencing approaches, we investigated 40 SCA17/TBP All except 1 (30/31) of the index cases with TBP Our data reveal an unexpected genetic interaction between STUB1 and TBP in the pathogenesis of SCA17 and raise questions on the existence of SCA48 as a monogenic disease with crucial implications for diagnosis and counseling. They provide a convincing explanation for the incomplete penetrance of intermediate TBP alleles and demonstrate a dual inheritance pattern for SCA17, which is a monogenic dominant disorder for TBP
Identifiants
pubmed: 34906452
pii: S1098-3600(21)01117-5
doi: 10.1016/j.gim.2021.08.003
pii:
doi:
Substances chimiques
Peptides
0
TATA-Box Binding Protein
0
TBP protein, human
0
polyglutamine
26700-71-0
STUB1 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
29-40Informations de copyright
Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.