Molecular basis of albinism: Mutations and polymorphisms of pigmentation genes associated with albinism

Tang

Proc. Natl. Acad. Sci. U.S.A.

et al. 2005

Section: Ammalian Presenilins (Ps) Consists Of Two Homologous Pro-mentioning

confidence: 88%

Regulation of tyrosinase trafficking and processing by presenilins: Partial loss of function by familial Alzheimer's disease mutation

Tang

Proc. Natl. Acad. Sci. U.S.A.

et al. 2005

“…Most of the mutations tend to occur in the C-terminal half of the polypeptide, which contains the majority of the membrane-spanning domains. 20 Polymorphism within the OCA2 gene is significantly associated with eye color 21 and also underlies the previous assignment of the brown eye (BEY2/EYCL3, MIM227220) and brown hair (HCL3, MIM601800) phenotypes. A single single-nucleotide polymorphism in the neighboring gene, HERC2, was recently found to be a common founder polymorphism affecting an OCA2 regulatory element, which in turn results in blue eye color 22,23 and reduced melanin content in cultured human melanocytes.…”

Section: Introductionmentioning

confidence: 83%

“…25 Type I OCA has been extensively studied and divided into two clinical subtypes; OCA1A is caused by the complete loss of catalytic activity of the tyrosinase enzyme (TYR) and results in the life-long absence of melanin pigment, whereas OCA1B retains residual tyrosinase function allowing for the development of some melanin pigment. 20,26 The two other forms of albinism, OCA3 and OCA4, have been found to result from mutations in the TYRP1 and SLC45A2 gene loci, respectively. The TYRP1 locus has been mapped to chromosome 9p23, and 95% of OCA3-related mutations result in the generation of premature stop codons or frameshifts producing truncated proteins.…”

Section: Introductionmentioning

confidence: 99%

Inheritance of a novel mutated allele of the OCA2 gene associated with high incidence of oculocutaneous albinism in a Polynesian community

et al. 2009

Oculocutaneous albinism type 2 (OCA2) is a human autosomal-recessive hypopigmentation disorder associated with pathological mutations of the OCA2 gene. In this study, we investigated a form of OCA in a Polynesian population with an observed phenotype characterized by fair skin, some brown nevi present in the sun-exposed areas and green or blue eyes. Hair presented with a unique red coloration since birth, with tones ranging across individuals from Yellow-Red to Brown-Red, or Auburn. We genetically screened for mutations in the OCA2 and MC1R genes as their products have previously been shown to be associated with red hair/fair skin and OCA2. The SLC45A2 gene was also screened to identify any possible relation to skin color variation. We have identified a novel missense substitution in the OCA2 gene (Gly775Asp) responsible for OCA2 in individuals of Polynesian heritage from Tuvalu. The estimated incidence of this form of OCA2 in the primary study community is believed to occur at one of the highest recorded rates of albinism at approximately 1 per 669 individuals. In addition, we have analyzed four unrelated individuals with albinism who have Polynesian heritage from three other separate communities and found they carry the same OCA2 mutation. We also analyzed an out-group comprising three unrelated individuals with albinism of Melanesian ancestries from two separate communities, one Australian Aboriginal and three Australian Caucasians, and did not detect this mutation. We hypothesize that this mutation may be Polynesian specific and that it originated from a common founder.

“…23 OCA2, an autosomal recessive gene that is responsible for type 2 oculocutaneous albinism, is currently attributed toward the hypopigmentation phenotype seen in type I (deletion) AS patients as it lies within the AS deletion region along 15q11-q13. 24,25 However, this does not explain why other AS patients with UBE3A mutations, imprinting defect along 15q11-q13 or paternal uniparental disomy (type II-IV), which have intact OCA2, still show to a certain extent, the hypopigmentation phenotype. 26 Gene expression in AS mouse cerebellum used in this study may be different from gene expression in other tissues such as the skin, even though neurons and skin are derived from the same lineage cells.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide gene expression profiling of the Angelman syndrome mice with Ube3a mutation

Low

Chen

2010

Eur J Hum Genet

Angelman syndrome (AS) is a human neurological disorder caused by lack of maternal UBE3A expression in the brain. UBE3A is known to function as both an ubiquitin-protein ligase (E3) and a coactivator for steroid receptors. Many ubiquitin targets, as well as interacting partners, of UBE3A have been identified. However, the pathogenesis of AS, and how deficiency of maternal UBE3A can upset cellular homeostasis, remains vague. In this study, we performed a genome-wide microarray analysis on the maternal Ube3a-deficient (Ube3a mÀ/p+ ) AS mouse to search for genes affected in the absence of Ube3a. We observed 64 differentially expressed transcripts (7 upregulated and 57 downregulated) showing more than 1.5-fold differences in expression (Po0.05). Pathway analysis shows that these genes are implicated in three major networks associated with cell signaling, nervous system development and cell death. Using quantitative reverse-transcription PCR, we validated the differential expression of genes (Fgf7, Glra1, Mc1r, Nr4a2, Slc5a7 and Epha6) that show functional relevance to AS phenotype. We also show that the protein level of melanocortin 1 receptor (Mc1r) and nuclear receptor subfamily 4, group A, member 2 (Nr4a2) in the AS mice cerebellum is decreased relative to that of the wild-type mice. Consistent with this finding, expression of small-interfering RNA that targets Ube3a in P19 cells caused downregulation of Mc1r and Nr4a2, whereas overexpression of Ube3a results in the upregulation of Mc1r and Nr4a2. These observation help in providing insights into the genesis of neurodevelopmental phenotype of AS and highlight specific area for future research.