15q13.1 View the map and BAC clones (data from UCSC genome browser).
Note that the human P gene corresponds to the region within the chromosome segment 15q11-q13, which is typically deleted in patients with Prader-Willi and Angelman syndrome.
OCA2/NM_000275: 24 exons, 344,434bp, Chr15: 25,602,392 - 25,946,825.
The figure below shows the structure of the OCA2 gene (data from UCSC genome browser).
Search the 5'UTR and 1kb upstream regions (human and mouse) by CONREAL with 80% Position Weight Matrices (PWMs) threshold (view results here).
Tissue specificity: Varied expression, highest in brain.
BMR: Bone marrow; SPL: Spleen; TMS: Thymus; BRN: Brain; SPC: Spinal cord; HRT: Heart; MSL: Skeletal muscle; LVR; Liver; PNC: Pancreas; PST: Prostate; KDN: Kidney; LNG: Lung. (data from GeneCards )
|Protein||NP_068679 (833aa)||13636 (128aa)||NP_608878 (846aa)||XP_320080 (580aa)|
|Identities||78% /659aa||59% /76aa||40% /232aa||51% /266aa|
View multiple sequence alignment (PDF file) by ClustalW and GeneDoc.
(1) Domains predicted by SMART:
a) low complexity 123 - 135
b) transmembrane 175 - 197
c) transmembrane 327 - 346
d) transmembrane 353 - 370
e) transmembrane 385 - 407
f) transmembrane 420 - 439
g) transmembrane 508 - 530
h) low complexity 580 - 591
i) transmembrane 621 - 643
j) transmembrane 648 - 667
k) transmembrane 679 - 701
l) transmembrane 721 - 739
m) transmembrane 777 - 799
n) transmembrane 814 - 836
(2) Transmembrane domains predicted by SOSUI: 12 transmembrane helices detected.
|No.||N terminal||transmembrane region||C terminal||type||length|
(3) Graphical view of InterPro domain structure.
(1) Predicted results by ScanProsite:
a) Amidation site : [occurs frequently]
7 - 10: dGRR, 33 - 36: aGKR.
b) Protein kinase C phosphorylation site : [occurs frequently]
86 - 88: SsR, 153 - 155: SeK, 303 - 305: SiR, 453 - 455: TiR.
c) N-glycosylation site : [occurs frequently]
214 - 217: NYSV, 218 - 221: NLSS, 273 - 276: NWTV, 442 - 445: NVTT, 754 - 757: NLSH, 781 - 784: NGTL.
(2) Predicted results of subprograms by PSORT II:
a) Seems to have no N-terminal signal peptide
b) KDEL ER retention motif in the C-terminus: none
c) ER Membrane Retention Signals: none
d) VAC possible vacuolar targeting motif: none
e) Actinin-type actin-binding motif: type 1: none; type 2: none
f) Prenylation motif: none
g) memYQRL transport motif from cell surface to Golgi: none
h) Tyrosines in the tail: none
i) Dileucine motif in the tail: none
This protein does not exist in the current release of SWISS-2DPAGE.
Computed theoretical MW=92,894Da, pI=6.72 (NP_000266).
a) Biological process: eye pigment biosynthesis
b) L-tyrosine, eye pigment precursor, and arsenite transporter activity
c) Serine-type endopeptidase inhibitor activity
d) Integral to membrane
e) Belongs to the SLC13A family of transporters (P subfamily).
Integral membrane protein. Steady-state melanosomal localization requires a conserved consensus acidic dileucine-based sorting motif within the cytoplasmic N-terminal region of OCA2. A second dileucine signal within this region confers steady-state lysosomal localization in melanocytes (Sitaram, et al).
The P protein regulates posttranslational processing and transport of tyrosinase (Chen, et al; Toyofuku, et al).
No entries in the CuraGen Drosophila interaction database for CG15624.
The P protein is believed to be an integral membrane protein involved in small molecule transport, specifically tyrosine - a precursor of melanin. P protein plays an important role in the generation or maintenance of melanosomal pH, which is required for the tyrosinase activity and the assembly of the normal melanogenic complex (Puri, et al). P protein increases cellular sensitivity to arsenicals and other metalloids and can modulate intracellular glutathione metabolism (Staleva, et al).
The distribution of mutations and polymorphisms is described in detail in Albinism Database. For cross-reference, view the distribution of the same set of mutations and polymorphisms in the Retina International Mutation Database of P-Gene.
Except the mutations deposited in the HGMD database, 44 additional mutations are listed here.
(1) Duan, et al and Li, et al have reported four novel mutations (N476D, G775R, A787T, Y827H) in the P gene in Chinese OCA2 patients.
(2) Three mutations in P (V443I, N476S, C793F) were identified by Preising, et al.
(3) An Thai-Chinese OCA2 patient was compound heterozygous for two novel splice site mutations, a paternally inherited IVS9 + 1delG, and a maternally inherited IVS23 + 1G >A (Wattanasirichaigoon, et al).
(4) Hutton, et al (2008) reported one novel mutation (I634N) in a non-Hispanic Caucasian OCA2 patient.
(5) Dai, et al reported one novel mutations (T450M) in the P gene in Chinese OCA2 patients.
(6) Rooryck, et al (2008) reported 12 novel mutations including six missense (H249D, G485V, A558P, S732L, P743R, R811S), two frameshift (c.898insG, c.2106delinsTTC), one splicing (c. 1116 +6T>C), one nonsense mutation (W61X), and two deletions spanning exons 3-20.
(7) Gronskov, et al (2009) reported 6 novel mutations (c.157delA, E96A, Y342C, Y415H, C626R, L727P) in Danish OCA or AROA patients.
(8) Wei, et al (2010) reported 14 previously unreported mutational alleles (c.168delC, c.980insT, c.860_883del24 bp, c.2351_2376del26 bp, p.R136X, p.K155N, p.R243C, p.Q321P, p.C430X, p.T450K, p.R455G, p.R555C, p.A776D, and p.G782R) in Chinese Han OCA patients. The most frequent allele in this screen was p.R455G, which accounts for 15% of the mutational OCA2 alleles in this population.
(9) Johanson, et al (2010) identified one novel mutation (p.G775D) in Polynesian OCA2 patients.
Most missense mutations of the p gene are located within the loops between the TM domains. Genotype-phenotype relationship is not well defined.
Defects in OCA2 are the cause of oculocutaneous albinism type II (OCA2) (Rinchik, et al) (OMIM 203200). OCA2 is an autosomal recessive form of albinism, a disorder of pigmentation in the skin, hair, and eyes. The phenotype of patients with OCA2 is typically somewhat less severe than in those with tyrosinase-deficient OCA1. There are several forms of OCA2, from typical OCA to relatively mild 'autosomal recessive ocular albinism' (AROA) (OMIM 203310). OCA2 belongs to tyrosinase-positive oculocutaneous albinism. OCA2 patients are usually born with minimal pigmentation and become darker during adulthood, finally showing minimal-to-moderate pigmentation of their skin, hair and eyes.
OCA2 is about twice as common as OCA1 in African and African-American populations. The frequency of OCA2 is greatly increased in patients with Prader-Willi or Angelman syndrome (Lee, et al). Recent studies have shown that OCA2 is not the most frequent OCA subtype in some populations. In Chinese, Japanese and Caucasian patients, the most prevalent form of OCA is OCA1, whereas OCA2 and OCA4 are much less frequent and OCA3 virtually non-existent (Hutton, et al (2008); Suzuki, et al (2008); Rooryck, et al (2008); Gronskov, et al (2009); Wei, et al (2010) ). Genome-wide association studies have shown that OCA2 is associated with the colors of human skin, hair and iris (Han, et al). The non-synonymous polymorphism rs1800414 (His615Arg) located within the OCA2 gene is significantly associated with skin pigmentation in East Asian populations (Edwards, et al).