| Affiliation: | 1. Diagnostic and Research Institute of Human Genetics, Medical University of Graz, Graz, Austria;2. Gottfried Schatz Research Center, Department of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria;3. Division of Haematology, Medical University of Graz, Graz, Austria;4. Neurogenetics Laboratory, Department of Neurology, Medical University of Graz, Graz, Austria;5. Gomal Centre of Biochemistry and Biotechnology, Gomal University, Dera Ismail Khan, Pakistan;6. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gomal University, Dera Ismail Khan, Pakistan;7. Department of Biological Sciences, Gomal University, Dera Ismail Khan, Pakistan;8. Gottfried Schatz Research Center, Department of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria BioTechMed Graz, Graz, Austria;9. Pediatric Orthopedic Department, Speising Hospital, Vienna, Austria |
| 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. |
