Analysis of a non‐lethal biallelic frameshift mutation in ZMPSTE24 reveals utilization of alternative translation initiation codons

Medientyp: E-Artikel
Titel: Analysis of a non‐lethal biallelic frameshift mutation in ZMPSTE24 reveals utilization of alternative translation initiation codons
Beteiligte: Kaufmann, Lukas; Pilic, Johannes; Auinger, Lisa; Mayer, Anna‐Lena; Blatterer, Jasmin; Semmler‐Bruckner, Johann; Abbas, Safdar; Rehman, Khurram; Ayaz, Muhammad; Graier, Wolfgang F.; Malli, Roland; Petek, Erwin; Wagner, Klaus; Al Kaissi, Ali; Khan, Muzammil Ahmad; Windpassinger, Christian
Erschienen: Wiley, 2023
Erschienen in: Clinical Genetics
Sprache: Englisch
DOI: 10.1111/cge.14381
ISSN: 0009-9163; 1399-0004
Schlagwörter: Genetics (clinical) ; Genetics
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Beschreibung: <jats:title>Abstract</jats:title><jats:p>Restrictive dermopathy (RD) is a lethal condition caused by biallelic loss‐of‐function mutations in <jats:italic>ZMPSTE24</jats:italic>, 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 <jats:italic>ZMPSTE24</jats:italic> [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.</jats:p>

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