Mutations of the human P gene associated with type II oculocutaneous albinism (OCA2)

Abstract

Mutations in the human P gene lead to oculocutaneous albinism type 2 (OCA2, MIM #203200), the most common type of albinism in humans. The P gene encodes a 110 kDa protein that is associated with melonosomal membranes and contains 12 potential membrane spanning domains. The specific function of the P protein is currently unknown. We report 7 new mutations in the P gene associated with OCA2. This includes 6 missense mutations (S86R, C112F, A368V, T592I, A724P and A787V) and one frameshift mutation (1047del7). We also report 8 polymorphisms including one amino acid substitution, D/A257. We and others have found many polymorphisms of the P gene in the coding region, several of which result in amino acid substitutions, making molecular diagnosis problematic. In contrast to this is the tyrosinase gene associated with OCA1, with a limited number of polymorphic variations in the coding region. There is also no apparent clustering of P gene missense mutations in contrast to the clustering observed by the tyrosinase gene missense mutations that define functional domains of the protein. Further mutational analysis is needed to help define the critical functional domains of the P protein and to allow a definitive diagnosis of OCA2.

The Mouse p (pink‐eyed dilution) and Human P Genes, Oculocutaneous Albinism Type 2 (OCA2), and Melanosomal pH

“…OCA1 is associated with mutations in the tyrosinase gene (69), reviewed by Oetting (9). The other common form is OCA2, associated with mutations in the P gene (20,21,(70)(71)(72)(73)(74)(75)(76), the latter being the most common form of albinism (68). The cutaneous phenotype of OCA2 is broad, ranging from minimal to moderate pigmentation of the hair, skin, and iris, with minimal ability to tan (68).…”

“…The P gene is encoded by 24 exons (plus one alternate exon that contains an in-frame stop codon corresponding to IR10-1, an anonymous genomic clone) that spans approximately 250-650 kb of genomic DNA (22). The human proximal promoter region contains sequences that might be used as binding sites for transcription factors, including the following motifs: one AP4 site, four discrete and one complex AP2 site, one CF1 site, one (14,76,89). The missense mutations described to date do not seem to cluster in any specific region of the peptide, as observed for tyrosinase, but most mutations described so far are in the carboxy half of the polypeptide that contains the majority of the 12 membrane spanning domains.…”

The Tyrosinase Gene and Oculocutaneous Albinism Type 1 (OCA1): A Model for Understanding the Molecular Biology of Melanin Formation

“…These mutations include missense, nonsense, frameshift, and splice site mutations, and a deletion of the entire coding sequence (21,46) At present, only three polymorphisms in the coding region have been identified, two of which, 192Y/S and 402R/Q, have relatively high allele frequencies for the minor alleles (21). This is different from the P gene, associated with OCA2, which has numerous reported polymorphisms in the coding regions and intron/ exon boundaries (47)(48)(49). There are also four reported polymorphisms in the promoter region, − 199C/A, −259G/C, −301C/T and the (GA)n dinucleotide repeat at −1000 bp, but no putative mutations have been identified.…”