Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Kaufmann, L; Pilic, J; Auinger, L; Mayer, AL; Blatterer, J; Semmler-Bruckner, J; Abbas, S; Rehman, K; Ayaz, M; Graier, WF; Malli, R; Petek, E; Wagner, K; Al, Kaissi, A; Khan, MA; Windpassinger, C.
Analysis of a non-lethal biallelic frameshift mutation in ZMPSTE24 reveals utilization of alternative translation initiation codons.
Clin Genet. 2023; 104(4):491-496
Doi: 10.1111/cge.14381
Web of Science
PubMed
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- Führende Autor*innen der Med Uni Graz
- Kaufmann Lukas
- Windpassinger Christian
- Co-Autor*innen der Med Uni Graz
- Auinger Lisa
- Blatterer Jasmin
- Graier Wolfgang
- Malli Roland
- Mayer Anna-Lena
- Petek Erwin
- Pilic Johannes
- Semmler-Bruckner Johann
- Wagner Klaus
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- Abstract:
- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Humans - administration & dosage
- Frameshift Mutation - genetics
- Codon, Initiator - genetics
- Metalloendopeptidases - genetics, metabolism
- Mutation - administration & dosage
- Codon - administration & dosage
- Membrane Proteins - genetics
- Find related publications in this database (Keywords)
- alternative start codon
- genotype-phenotype correlation
- lethal restrictive dermopathy
- mandibuloacral dysplasia
- mutation analysis
- progeria
- variant interpretation