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

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.

Automated summary

Restrictive dermopathy (RD) is a lethal condition caused by loss-of-function mutations in ZMPSTE24, while mutations preserving residual enzymatic activity lead to mandibuloacral dysplasia with type B lipodystrophy (MADB) phenotype. A new homozygous loss-of-function mutation in ZMPSTE24 was identified in two consanguineous Pakistani families with MADB. Functional analysis revealed that alternative translation initiation sites were utilized, preventing complete loss of protein function and explaining the relatively mild phenotype in affected patients. Our findings suggest considering the creation of new potential start codons in other disease-associated genes with N-terminal mutations.