A novel missense mutation of the DSRAD gene in a Chinese family with dyschromatosis symmetrica hereditaria

ARTICLE

Auteur(s) : Yingying Dong¹, Shengxiang Xiao¹, Jianwen Ren¹, Jia Huo¹, Yan Liu¹, Xiaoli Li¹

Department of Dermatology, Second Hospital of Xi’an Jiaotong University, 157 Xi Wu Road, Xi’an, Shaanxi, 710004, China

Dyschromatosis symmetrica hereditaria (DSH; MIM127400) is an autosomal dominant skin disorder characterized by a mixture of hyperpigmented and hypopigmented macules of various sizes on the back of the hands and feet. Many patients with DSH also have small freckle-like pigmented macules on their faces. These clinical features usually appear in infancy or early childhood, commonly stop spreading before adolescence, and last for life. The DSH locus has been mapped to chromosome 1q21 and then, in 2003, pathogenic mutations were identified in the double-stranded RNA-specific adenosine deaminase (DSRAD) gene [1, 2]. Now, more than 70 mutations including missense substitutions, deletions, insertions and nonsense mutations at various regions of this gene have been reported in Japanese and Chinese people [3].

In this study, we performed mutation detection of the DSRAD gene in a typical three-generation Chinese family with DSH, in which a novel missense mutation was identified. The Human Medical and Ethical Committee of Xi’an Jiaotong University approved the investigation presented here, and the patient and family gave their informed consent.

The DSH pedigree showed an autosomal dominant inheritance pattern (figure 1A). The proband was a 12-year-old girl. She had asymptomatic hypopigmented small macules on the extensor aspect of her fingers and toes when she was born, and then a mixture of hyperpigmented and hypopigmented macules appeared on the dorsal aspect of her hands and feet (figure 1B). These lesions were irregular in shape and size. She also had freckles on her face. The skin lesions became more pronounced after sun exposure. The other affected members had also developed a mixture of hypopigmented and hyperpigmented macules of various sizes on the dorsal aspects of their extremities since childhood.

Five milliliters of peripheral blood were collected from the proband and also her grandfather, father, uncle, aunt and 50 unrelated people. Genomic DNA was extracted from peripheral blood and used as a template for the polymerase chain reaction (PCR) amplification of all 15 exons of the DSRAD gene. We carried out mutation scanning by direct sequencing of PCR products. Sequences were compared with those of unaffected members and 50 unrelated samples.

The results of sequencing the PCR products from proband are shown in (figure 1C). A novel nucleotide c.3,073A>G missense mutation was found, which changes codon 958 from histidine (CAT) to arginine (CGT). The same mutation was also found in her grandfather and father, but not in the healthy individuals of the family and 50 unrelated controls (figure 1D) [DSRAD GenBank sequences used: NM_001111].

The DSRAD contains 15 exons and is composed of 1226 amino acid residues. It contains at least six functional domains: Two Z-alpha domains, three dsRNA-binding domains and the putative deaminase domain, which are located in exon 2, exons 2-7 and exons 9-14 respectively [4]. The deaminase domain of the DSRAD protein is located in the codon from 886 to 1,221, which is approximately 30% of the full length of the DSRAD protein. These results suggest that the deaminase domain might be a hot spot for mutations [5]. The missense mutation c.3073A>G alters a conserved amino acid residue at 958 in exon 10, which is located in the putative deaminase domain, so the amino acid residue at 958 is suspected to play an important role in the conformation of the catalytic site of the enzyme, and the mutation at this position could probably compromises enzyme activity [6].

In conclusion, the results provide an addition to the DSH mutation database and will contribute further to the understanding of DSH genotype/phenotype correlations and to the pathogenesis of this disease. In a future study, we will construct the p.H958R mutant of DSRAD, and explore the pathogenesis of DSH.

Acknowledgements

References

2 He PP, He CD, Cui Y, et al. Refined localization of dyschromatosis symmetrica hereditaria gene to a 9Æ4-cM region at 1q21–22 and a literature review of 136 cases reported in China. Br J Dermatol 2004; 150: 633-9.

3 Ren JW, Luo SJ, Peng ZH, Liu Y, Pan M, Xiao SX. Novel frameshift mutation of the DSRAD gene in a Chinese family with dyschromatosis symmetrica hereditaria. J Eur Acad Dermatol Venereol 2008; 22: 1375-6.

4 Wang Y, Zeng Y, Murray JM, Nishikura K. Genomic organization and chromosomal location of the human dsRNA adenosine deaminase gene: the enzyme for glutamate-activated ion channel RNA editing. J Mol Biol 1995; 254: 184-95.

5 Suzuki N, Suzuki T, Inagaki K, et al. Ten novel mutations of the ADAR1 gene in Japanese patients with dyschromatosis symmetrica hereditaria. J Invest Dermatol 2006; 127: 309-11.

6 Miyamura Y, Suzuki T, Kono M, et al. Mutations of the RNA-specific adenosine deaminase gene (DSRAD) are involved in dyschromatosis symmetrica hereditaria. Am J Hum Genet 2003; 73: 693-9.

1 These authors all contributed equally to this work.