Novel Mutations of ABCB6 Associated with Autosomal Dominant Dyschromatosis Universalis Hereditaria

Ying-Xia Cui,Wei-Ping Wang,Hong-Lin Yin,Xiao-Buo Fan,Tong Ni,Xue-Jun Shang,Shao-Jun Jiang,Yang Zhou,Lin Gao,Xin-Yi Xia,Gang Wang,Xiao-Jun Li,Yu-An Hu,Bing Yao,Markus Schuelke

doi:10.1371/journal.pone.0079808

Abstract

ObjectiveDyschromatosis universalis hereditaria (DUH) is a rare heterogeneous pigmentary genodermatosis, which was first described in 1933. The genetic cause has recently been discovered by the discovery of mutations in ABCB6. Here we investigated a Chinese family with typical features of autosomal dominant DUH and 3 unrelated patients with sporadic DUH.MethodsSkin tissues were obtained from the proband, of this family and the 3 sporadic patients. Histopathological examination and immunohistochemical analysis of ABCB6 were performed. Peripheral blood DNA samples were obtained from 21 affected, 14 unaffected, 11 spouses in the family and the 3 sporadic patients. A genome-wide linkage scan for the family was carried out to localize the causative gene. Exome sequencing was performed from 3 affected and 1 unaffected in the family. Sanger sequencing of ABCB6 was further used to identify the causative gene for all samples obtained from available family members, the 3 sporadic patients and a panel of 455 ethnically-matched normal Chinese individuals.ResultsHistopathological analysis showed melanocytes in normal control’s skin tissue and the hyperpigmented area contained more melanized, mature melanosomes than those within the hypopigmented areas. Empty immature melanosomes were found in the hypopigmented melanocytes. Parametric multipoint linkage analysis produced a HLOD score of 4.68, with markers on chromosome 2q35-q37.2. A missense mutation (c.1663 C>A, p.Gln555Lys) in ABCB6 was identified in this family by exome and Sanger sequencing. The mutation perfectly cosegregated with the skin phenotype. An additional mutation (g.776 delC, c.459 delC) in ABCB6 was found in an unrelated sporadic patient. No mutation in ABCB6 was discovered in the other two sporadic patients. Neither of the two mutations was present in the 455 controls. Melanocytes showed positive immunoreactivity to ABCB6.ConclusionOur data add new variants to the repertoire of ABCB6 mutations with DUH.

Highlights

Dyschromatosis universalis hereditaria (DUH) is a group of heterogeneous pigmentary genodermatosis characterized by asymptomatic hypo- and hyper-pigmented macules of irregular size and shape which appear early in life; DUH most often manifests within the first year of life
We suggest that the mutations c.1663CA and c.459 delC of ABCB6 be the genetic cause of the disease in the patients with the familial and the sporadic DUH
Recent studies have revealed that ABCB6 is glycosylated in multiple cell types and it is localized in the endoplasmic reticulum, Golgi apparatus, lysosome, and plasma membrane, rather than in the mitochondria [19,20]

Summary

Introduction

Dyschromatosis universalis hereditaria (DUH) is a group of heterogeneous pigmentary genodermatosis characterized by asymptomatic hypo- and hyper-pigmented macules of irregular size and shape which appear early in life; DUH most often manifests within the first year of life. DUH was first described in 1933 by Ichikawa and Higari [1] and was most commonly reported in Japan [2], but it was reported in other Asian countries, Europe, South America, and Africa [3,4,5,6,7,8,9,10]. DUH was classified into two subtypes, DUH 1 (OMIM, 127500), an autosomal dominant disease, and DUH 2 (OMIM, 612715) an autosomal recessive disease. DUH with autosomal dominant transmission is generally reported. The locus for autosomal dominant DUH has been reported at chromosome 6q24-q25.2, between D6S1703 and D6S1708, spanning 10.2.Mbp [11]. Zhang and colleagues have reported that ABCB6 mutations are responsible for DUH [12].

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