Seven novel mutations of ADAR in multi-ethnic pedigrees with dyschromatosis symmetrica hereditaria in China

Abstract

Background: Dyschromatosis symmetrica hereditaria (DSH;OMIM: #127400) is a rare autosomal dominant skin disease of hyperpigmented and hypopigmented macules on the dorsal aspects of the feet and hands. The adenosine deaminase RNA-Specific (ADAR;OMIM: *146920) gene was identified as causing DSH. Although more than 200 mutations are reported, no research has included the pedigrees of ethnic minorities in China. To investigate clinical features and genetic factors among multi-ethnic families, seven multi-ethnic pedigrees with DSH were collected for analysis of hereditary characteristics and ADAR mutations.

Methods: All 15 exons and exon-intron sequences of the ADAR gene were amplified and Sanger sequenced from 25 patients and 36 normal controls from seven multi-ethnic DSH families with 100 healthy normal controls. Seven mutations were analyzed by Polyphen 2, SIFT and Provean. All mutations in ADAR with DSH were reviewed and genetic and clinical features were summarized for analysis. The ADEAMc domain may be a hot spot of ADAR mutations among patients with DSH.

Results: Seven novel mutations were identified in seven multi-ethnic pedigrees: c.497delA(p.Arg105fs), c.3352C>T(p.Gln1058*) and c.3722delT(p.Ser1181fs) were found in three Uygur families with DSH; c.1330A>G(p.Val332Met) and c.2702A>T(p.His841Leu) were found in two Kazakh pedigrees and c.1176G>A(p.Lys326Glu) and c.2861G>A(p.Arg892His) in two Hui pedigrees. We summarized 203 different mutations of ADAR from people with DSH.

Conclusions: Seven novel mutations were identified in seven multi-ethnic families with DSH. Our study expands the genetic spectrum of ADAR mutations in DSH.

Keywords: China; adenosine deaminase acting on RNA; dyschromatosis symmetrica hereditaria; mutation.

Figure 1

The family diagram: three Uyghur population families (a–c), two Hasakez population families (d, e) and two Hui population families (f, g)

Figure 2

Mutations of the ADAR1 gene in multi‐ethnic pedigrees with DSH in China were seven novel mutations including four missense mutations (p.K326E, p.H841L, p.V332M and p.R892H), frameshift mutations (p.R105fs and p.S1181fs) and one nonsense mutation (p.G1058*) in seven pedigrees from different ethnicities

Figure 3

ADAR1 sequence comparison among multispecies using UniProtKB showed mutation regions located in conservative regions

Figure 4

Patients in this study had a typical mixture of hyperpigmented and hypopigmented macules on the dorsal aspect of hands and feet

Figure 5

Two‐hundred and three different mutations of the ADAR1 gene for DSH