THE MOUSE PINK-EYED DILUTION GENE - ASSOCIATION WITH HYPOPIGMENTATIONIN PRADER-WILLI AND ANGELMAN SYNDROMES AND WITH HUMAN OCA2

Mutations at the mouse pink-eyed dilution locus, p, cause hypopigmenta tion. We have cloned the mouse p gene cDNA and the cDNA of its human c ounterpart, P. The region of mouse chromosome 7 containing the p locus is syntenic with human chromosome 15q11-q13, a region associated with Prader-Willi syndrome (PWS) and Angelman syndrome (AS), both of which involve profound imprinting effects. PWS patients lack sequences of p aternal origin from 15q, whereas AS patients lack a maternal copy of a n essential region from 15q. However, the critical regions for these s yndromes are much smaller than the chromosomal region commonly deleted that often includes the P gene. Hypopigmentation in PWS and AS patien ts is correlated with deletions of one copy of the human P gene that i s highly homologous with its mouse counterpart. A subset of PWS and AS patients also have OCA2. These patients lack one copy of the P gene i n the context of a PWS or AS deletion, with a mutation in the remainin g chromosomal homologue of the P gene. Mutations in both homologues of the P gene of OCA2 patients who do not have PWS or AS have also been detected.