Molecular bases of congenital hypopigmentary disorders in humans and oculocutaneous albinism 1 in Japan

The molecular bases of various types of congenital hypopigmentary disorders have been clarified in the past 10 years. Homozygous gene mutations of enz ymes functional in melanogenesis such as tyrosinase, P protein and DHICA ox idase. result in oculocutaneous albinism (OCA) 1, OCA 2, and OCA 3, respect ively. The genes responsible for Hermansky-Pudlak syndrome (HPS) and Chedia k-Higashi syndrome (CHS) have also recently been isolated and cloned. The t ranscription factor paired bo 3 (PAX3) works at the promoter region of the microphthalmia-associated transcription factor (MITF) gene, and the MITF tr anscription factor orders the expression of c-kit. which encodes the recept or for stem-cell factor, which in turn stimulates melanoblast migration fro m the neural tube to the skin in the embryo. Heterozygous mutations of PAX3 , MITF or c-kit genes induce Waardenburg syndrome (WS) 1/3, WS 2 or Piebald ism, respectively. A defect of endothelin-3 or the endothelin-B receptor pr oduces WS 4. In our examination of 26 OCA 1 patients in Japan, all were fou nd to have homozygous or heterozygous tyrosinase gene mutations at codons 7 7 or 310, Therefore, mutations at codons 77 and 310 are the major ones in J apanese patients with OCA 1. An autosomal dominant pigmentary disease of dy schromatosis symmetrica hereditaria (DSH) is well known in Japan, and is ch aracterized by a mixture of hypo- and hyper-pigmented macules of various si zes on the backs of the hands and feet. The disease gene and its chromosoma l localization have not been identified yet. Our trial of linkage analysis and positional cloning to determine the disease gene is presented.