MUTATIONS OF THE P-GENE IN OCULOCUTANEOUS ALBINISM, OCULAR ALBINISM, AND PRADER-WILLI-SYNDROME PLUS ALBINISM

Background. Type II (tyrosinase-positive) oculocutaneous albinism is a n autosomal recessive disorder that has recently been mapped to chromo some segment 15q11-q13. The frequency of this disorder is greatly incr eased in patients with Prader-Willi or Angelman syndrome, both of whic h involve deletions of chromosome 15q. The P protein is a transmembran e polypeptide that may transport small molecules such as tyrosine, the precursor of melanin. The P gene is located in chromosome segment 15q 11-q13. Methods. We studied the tyrosinase and P genes in three patien ts with type II oculocutaneous albinism, one of whom also had Prader-W illi syndrome, and in one patient with a milder syndrome known as auto somal recessive ocular albinism. Individual exons of these genes were amplified from the DNA of each patient by the polymerase chain reactio n and screened for mutations by simultaneous analyses of single-strand ed conformation polymerphisms and heteroduplexes and subsequent DNA se quencing. Results. Mutations of the P gene were identified in ail four patients. These included one frame shift, three missense mutations th at result in amino acid substitutions, and one mutation that affects R NA splicing. The patient with Prader-Willi syndrome plus albinism had a typical deletion of the paternal chromosome 15, rendering him hemizy gous for a maternally inherited mutant allele of the P gene. The child with ocular albinism was heterozygous for two different mutations in the P gene. Conclusions. Abnormalities of the P gene are associated wi th a wide range of clinical phenotypes, including type It oculocutaneo us albinism, albinism associated with the Prader-Willi syndrome, and a t least some cases of autosomal recessive ocular albinism.