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.

Biallelic mutations in ZMPSTE24 are known to be associated with autosomal recessive mandibuloacral dysplasia with type B lipodystrophy (MADB) and lethal restrictive dermopathy (RD), respectively. Disease manifestation is depending on the remaining enzyme activity of the mutated ZMPSTE24 protein. To date, complete loss of function has exclusively been reported in RD cases. In this study, we identified a novel N-terminal homozygous frameshift mutation (c.28_29insA) in a consanguineous family segregating with MADB. An in-depth analysis of the mutated sequence revealed, that the one base pair insertion creates a novel downstream in-frame start codon, which supposedly serves as an alternative translation initiation site (TIS). This possible rescue mechanism would explain the relatively mild clinical outcome in the studied individuals. Our findings demonstrate the necessity for careful interpretation of N-terminal variants potentially effecting translation initiation.

The molecular genetics of UV-Sensitive syndrome: A rare dermal anomaly.

Ultraviolet-sensitive syndrome is a rare skin disorder characterised by heterogeneous phenotypic spectrum of skin freckling, telangiectasia and acute sunburn. It usually has an autosomal recessive pattern. So far, only 18 patients from nine different families (Japanese, French, Israeli, Iranian and Pakistani) have been reported in scientific literature. Its precise prevalence is still unknown, but, according to an estimate, its prevalence ratio is 1:100,000 worldwide. Until now, only three genes have been reported to be involved in the syndrome; the Excision Repair Cross-Complementing, Group 6, the Excision Repair Cross-Complementing, Group 8 and the UV-Stimulated Scaffold Protein A (UVSSA). Among these genes, the last one is reported to be more prevalent among different ethnicities, including Pakistani. Physiologically, most of the syndrome genes are involved in the transcription-coupled nucleotide excision pathway. In order to reduce the disease severity, the patients are advised to use medicated skin moisturisers or sun-blocks, sunglasses and gloves, while going out in the sun to avoid sun exposure. The current narrative review was planned to discuss the molecular genetics and the mutational spectrum of the syndrome, and to describe the differential diagnosis of various related disorders in order to facilitate clinical researchers.

Exome sequence analysis in consanguineous Pakistani families inheriting Bardet-Biedle syndrome determined founder effect of mutation c.299delC (p.Ser100Leufs*24) in BBS9 gene.

BACKGROUND: Bardet-Biedl syndrome (BBS) is characterized by a heterogeneous phenotypic spectrum of retinopathy, intellectual disability (ID), obesity, polydactyly, and kidney dysfunctions as the major clinical features. Genetic investigations have reported 21 BBS genes, the products of which are mostly located at the centrosome, basal body or the ciliary transition zone. METHODS: In the present genetic report, we analyzed two apparently unrelated consanguineous BBS families from Dera Ismail Khan (D.I.Khan) district, Pakistan. Genetic mapping was performed using Whole exome sequencing and Sanger sequencing. RESULTS: Whole exome sequencing identified a recently reported single base deletion NM_001033604.1:c.299delC in the fourth exon of BBS9 in both families. The identified frameshift mutation is predicted to cause premature truncation of the expressed protein (p.Ser100Leufs*24). This mutation has previously been mapped in a consanguineous Pakistani family; therefore this is the second report of this particular mutation in two additional BBS families originating from different locations. CONCLUSION: We speculate the evolutionary significance of this mutation and assume its strong founder effect in the Khaisoori tribe of D.I.Khan. Based on these findings, we suggest developing a molecular diagnostic test that may be used for premarital and prenatal screening of families at risk of BBS.