An exceptional biallelic N-terminal frame shift mutation in ZMPSTE24 leads to non-lethal progeria due to possible utilization of a downstream alternative start codon

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

“…3,6 We recently reported the first homozygous frameshift mutation in ZMPSTE24, NM_005857.5:c.28_29insA, leading to the milder MADB phenotype in a Pakistani family, although the protein is predicted to be severely truncated [p.(Leu10Tyrfs*37)]. 7 Interestingly, we detected the same exceptional homozygous mutation in another large Pakistani family segregating MADB. To elucidate the mechanism by which this particular mutation escapes the expected lethal consequences, we conducted in vitro experiments using expression vectors containing different ZMPSTE24 mutants in this study.…”

“…In this study, we characterize a large Pakistani family displaying a severe form of MADB segregating the same homozygous, N‐terminal frameshift mutation (c.28_29insA) in ZMPSTE24 as previously identified in MADB patients of an additional Pakistani family 7 . Compared to other published MADB cases the observed phenotype includes severe, progressive thoraco‐lumbar kyphosis and bilateral distended loins which could be related to renal lesions (Figure 1B).…”

“…In silico modeling of wild type and N-terminally truncated ZMPSTE24 protein revealed no significant differences in protein structure and stability, underlining possible preservation of protein function of the studied mutation. 7 Therefore, we suggest that the two N-terminal ATG-codons (novel ATG and M13-codon) present in the mutated ZMPSTE24 sequence are only sparsely utilized as alternative translation initiation sites in affected individuals displaying MADB. The resulting ZMPSTE24 proteins, which show ER localization and maintain all known functional domains may exhibit intact enzymatic activity.…”

“…We recently reported the first homozygous frameshift mutation in ZMPSTE24 , NM_005857.5:c.28_29insA, leading to the milder MADB phenotype in a Pakistani family, although the protein is predicted to be severely truncated [p.(Leu10Tyrfs*37)] 7 …”

“…A 21.1 Mb copy-neutral absence of heterozygosity (AOH) region on chromosome 1 (chr1:26092274-47189052 [hg38]) indicating autozygosity was detected by SNP array analysis. The ZMPSTE24 gene, located within this region, was considered a candidate gene based on the observed mandibuloacral dysplasia phenotype and Sanger sequencing revealed the same homozygous frameshift mutation NM_005857.5:c.28_29insA, p.(Leu10Tyrfs*37), which we recentlyreported as novel disease-causing mutation 7. The identified mutation segregated with the disease phenotype in the studied family (Figure1C).Comparative haplotype analysis of affected individuals of both families revealed a common disease-haplotype spanning 1p34.3-p33 including ZMPSTE24.…”