Analysis of a non-lethal biallelic frameshift mutation in ZMPSTE24 reveals utilization of alternative translation initiation codons.
alternative start codon
genotype-phenotype correlation
lethal restrictive dermopathy
mandibuloacral dysplasia
mutation analysis
progeria
variant interpretation
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
revised:
12
05
2023
received:
27
03
2023
accepted:
23
05
2023
medline:
5
9
2023
pubmed:
4
6
2023
entrez:
4
6
2023
Statut:
ppublish
Résumé
Restrictive dermopathy (RD) is a lethal condition caused by biallelic loss-of-function mutations in ZMPSTE24, whereas mutations preserving residual enzymatic activity of the ZMPSTE24 protein lead to the milder mandibuloacral dysplasia with type B lipodystrophy (MADB) phenotype. Remarkably, we identified a homozygous, presumably loss-of-function mutation in ZMPSTE24 [c.28_29insA, p.(Leu10Tyrfs*37)] in two consanguineous Pakistani families segregating MADB. To clarify how lethal consequences are prevented in affected individuals, functional analysis was performed. Expression experiments supported utilization of two alternative translation initiation sites, preventing complete loss of protein function consistent with the relatively mild phenotypic outcome in affected patients. One of these alternative start codons is newly formed at the insertion site. Our findings indicate that the creation of new potential start codons through N-terminal mutations in other disease-associated genes should generally be taken into consideration in the variant interpretation process.
Substances chimiques
Codon, Initiator
0
Metalloendopeptidases
EC 3.4.24.-
monoaminocarboxydihydroborane
98169-69-8
Codon
0
ZMPSTE24 protein, human
EC 3.4.24.84
Membrane Proteins
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
491-496Informations de copyright
© 2023 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.
Références
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