Novel Mutations of ABCB6 Associated with Autosomal Dominant Dyschromatosis Universalis Hereditaria

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.

Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia

“…Prokudin et al (Prokudin et al 2014) also later reported an ABCB6 heterozygous variant in a patient with bilateral iris and fundus coloboma inherited from the unaffected father. In addition, heterozygous ABCB6 nonsynonymous variants have been identified in familial and sporadic cases with dyschromatosis universalis hereditaria (MIM#615402) (Cui et al 2013;Liu et al 2014;Zhang et al 2013). In humans, skin tissue and melanocytes express ABCB6 (Zhang et al 2013).…”

ABCB6 Resides in Melanosomes and Regulates Early Steps of Melanogenesis Required for PMEL Amyloid Matrix Formation

“…The etiopathology of DUH is not known. Lesions show a focal increase or decrease in melanin and melanosome content of melanocytes and keratinocytes of the basal layer, which is believed to be the consequence of a defect in melanosome production and/or distribution, rather than a disorder of melanocyte numbers 42,46,47 . Several associated conditions have been reported, including ocular abnormalities, photosensitivity, neurosensory hearing defects, mental retardation and erythrocyte, platelet and tryptophan metabolism abnormalities 48 .…”

“…To study the potential of ABCB6 to rescue the above described ultrastructural phenotype, we stably transfected MNT-1 cells with constructs encoding either wild-type (WT), an inactive (K629M) 17,41 or a DUH mutant (G579E) ABCB6 variant 42 Next, parental MNT-1 cells, as well as MNT-1 cells stably expressing ABCB6 variants were depleted for endogenous ABCB6 using an siRNA construct targeting a non-coding region of the gene (siABCB6#2). Western blot analysis of MNT-1 cell lysates revealed that efficient targeting of endogenous ABCB6 still allowed the overexpression of the different ABCB6 variants (Fig 3C) providing a model system for rescue experiments.…”

Functional Coupling of ATP-binding Cassette Transporter Abcb6 to Cytochrome P450 Expression and Activity in Liver

“…In the human population, there are many incompletely understood incidences of a functional association between ABCB6 and human disease (19,22,51). However, the mechanistic association between loss of ABCB6 function and the pathogenesis of the disease is not clear.…”