Clinical And Molecular Genetics Of Two Hereditary Pigment Abnormalities

Dyschromatosis is a disease characterized by hyperpigmentation and hypopigmentation, which could be clinically divided into dyschromatosis symmetrica hereditaria (DSH) and dyschromatosis universalis hereditaria (DUH).DSH is an autosomal dominant pigmentary disorder characterized by the presence of hyperpigmented and hypopigmented macules mostly on the dorsal of the extremities. Genetic studies have certified that the mutations in the adenosine deaminase, RNA-specific-1(ADAR1) gene are responsible for the disorder by Miyamura in2003. Two DSH cases were collected and respectively found two new mutation, c.1479C>G (p.Y493X) in exon2and c.2563-2566delCTGA in exon8, which led to a premature termination and produced a truncated ADAR1protein. Skin biopsy specimens of hyper-and hypo-pigmented macules on the back of the left foot were obtained from the patient II.The Toluidine blue staining showed that melanocytes were normal in quantity and continuously or separately located in the basal layer of the hyperpigmented lesion, the dendrite of melanocytes grows toward the lateral of the skin. And the melanocytes were remarkable reduced in the hypopigmented lesion with distribution disorder. And the electron microscopy was consistent with the Toluidine blue staining. In the hyperpigmented lesions, some small melanosomes scattered sparsely, and few or no melanosomes in the hypopigmented lesion.DUH was first described in1933by Ichikawa and Higari and was classified into two subtypes, DUHⅠ, an autosomal dominant disease, and DUH II an autosomal recessive disease. DUHⅡ is a group of heterogeneous pigmentary genodermatosis characterized by asymptomatic hypo-and hyper-pigmented macules of irregular size and shape scattering over the entire body. Here we investigated a Chinese family with typical features of autosomal dominant DUH and3unrelated patients with sporadic DUH. Parametric multipoint linkage analysis of the family revealed the genetic linkage regions on chromosomes2q35-q37.2, which spanned approximately17Mbp with a HLOD score of4.68. Combined information from linkage analysis with exome sequencing, four genes (USP40, ABCB6, SLC11A1and NCL) with novel heterozygous mutations were selected as candidate genes in this family and USP40, SLC11A1and NCL were further excluded by Sanger sequencing. A missense mutation g.5496C>A, c.1663C> A, p. Gln555Lys in exon11of ATP-binding cassette transporter subfamily B member6(ABCB6) was further identified in the21affected members, but absent in the14unaffected members from the family and completely cosegregated with the skin phenotype. An additional mutation in exon1of ABCB6(g.776delC, c.459delC) was detected in an unrelated sporadic patient with typical DUH, however, no mutation in ABCB6was found in the other two patients. Skin biopsy specimens of hyper-and hypo-pigmented macules were obtained from the DUH proband and one unrelated patient. Methylene blue staining of cutaneous tissues shows normal numbers of morphologically-intact melanocytes present in the basal layer in hypo-and hyper-pigmented skin areas. The content and distribution of mature melanosomes in hyperpigmented macule were similar to normal control, whereas the content in hypopigmented macule was less than normal control. Mature melanosomes were found in melanocytes from normal control tissue and the proband’s hyperpigmented area. Immature melanosomes in the stage II were found in the hypopigmented melanocytes. Therefore, it might be suggested that the mutations of ABCB6led to the defeciency of protein function, which affected the melanin synthesis and expression, further brought out the DUH.