Identification of a novel protein truncating mutation p.Asp98* in XPC associated with xeroderma pigmentosum in a consanguineous Pakistani family

Abstract Background Xeroderma pigmentosum (XP) is a rare genetic disorder, which is characterized by hyper‐sensitivity to solar ultraviolet (UV) radiation. Clinical consequences of sun exposure are skin lesions and an increased risk of developing skin cancer. Genetic studies have identified eight genes associated with xeroderma pigmentosum. The proteins encoded by these genes are mainly involved in DNA repair mechanisms. Methods Molecular genetic characterization of patients with xeroderma pigmentosum involved positional cloning methods such as homozygosity mapping and subsequent candidate gene analysis. Mutation screening was performed through Sanger DNA sequencing. Results and Discussion In this case study, we report a novel protein truncating mutation in XPC associated with autosomal recessive xeroderma pigmentosum in a consanguineous Pakistani family. Genetic mapping revealed a novel single base insertion of a thymine nucleotide NM_004628.4: c.291dupT (c.291_292insT) in the second exon of XPC. The identified mutation leads to a premature stop codon (TGA) at amino acid position 98 (p.Asp98*) and thus presumably results in a truncated protein. The Xeroderma pigmentosum, complementation group C (XPC) is located on 3p25.1 and encodes a protein involved in nucleotide excision repair. The identified mutation presumably truncates all functional domains of the XPC protein, which likely results in the loss of protein function. Conclusion The study expands the knowledge of the mutational spectrum of XPC and is valuable for genetic counseling of affected individuals and their families

Disruption of a Novel Gene (IMMP2L) by a Breakpoint in 7q31 Associated with Tourette Syndrome

Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder characterized by multiple motor and phonic tics. We identified a male patient with GTS and other anomalies. It was determined that he carried a de novo duplication of the long arm of chromosome 7 [46,XY,dup(7)(q22.1-q31.1)]. Further molecular analysis revealed that the duplication was inverted. The distal chromosomal breakpoint occurred between the two genetic markers D7S515 and D7S522, which define a region previously shown to be disrupted in a familiar case of GTS. Yeast and bacterial artificial chromosome clones spanning the breakpoints were identified by means of FISH analysis. To further characterize the distal breakpoint for a role in GTS, we performed Southern blot hybridization analysis and identified a 6.5-kb SacI junction fragment in the patient’s genomic DNA. The DNA sequence of this fragment revealed two different breaks in 7q31 within a region of ∼500 kb. IMMP2L, a novel gene coding for the apparent human homologue of the yeast mitochondrial inner membrane peptidase subunit 2, was found to be disrupted by both the breakpoint in the duplicated fragment and the insertion site in 7q31. The cDNA of the human IMMP2L gene was cloned, and analysis of the complete 1,522-bp transcript revealed that it encompassed six exons spanning 860 kb. The possible role of IMMP2L and several other candidate genes within the region of chromosomal rearrangement, including NRCAM, Leu-Rch Rep, and Reelin, is discussed. The 7q31 breakpoint interval has also been implicated in other neuropsychiatric diseases that demonstrate some clinical overlap with GTS, including autism and speech-language disorder