Seven novel mutations of the ADAR gene in Chinese families and sporadic patients with dyschromatosis symmetrica hereditaria (DSH)

Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant pigmentary genodermatosis characterized by hyperpigmented and hypopigmented macules of on the extremities and caused by the mutations in the ADAR gene(also called DSRAD) encoding for RNA-specific adenosine deaminase. Here we reported clinical and molecular findings of 6 Chinese multi-generation families and 2 sporadic patients with DSH. We found that the same mutation could lead to different phenotypes even in the same family and we did not establish a clear correlation between genotypes and phenotypes. Seven novel heterozygous mutations of ADAR were identified, which were c.2433_2434delAG (p.T811fs), c.2197G>T (p.E733X), c.3286C>T (p.R1096X), c.2897G>T (p.C966F), c.2797C>T (p.Q933X), c.2375delT (p.L792fs) and c.3203-2A>G respectively. Our data add new variants to the repertoire of ADAR mutations in DSH.     

Thirteen novel mutations in the NR0B1 (DAX1) gene as cause of adrenal hypoplasia congenita

X-linked adrenal hypoplasia congenita (AHC) is a rare developmental disorder associated with primary adrenal insufficiency and combined primary and secondary male hypogonadism. It is caused by deletions or mutations of the NR0B1 (DAX1) gene encoding DAX1, an atypical orphan member of the nuclear receptor superfamily. The continuous molecular genetic analysis of male patients with primary adrenal insufficiency revealed 13 novel mutations within the coding region of the NR0B1 gene which are predicted to inactivate the DAX1 function. These were three nonsense mutations (c.312C>A, p.Cys104X, c.670C>T, p.Gln224X; and c.873G>A, p.Trp291X), five duplications (c.269_270dup, c.421_422dup, c.895_896dup, c.989dup, c.999_1000dup), and five deletions (c.483del, c.745_746del, c.734_740del, c.1092del, and c.1346del). All of the mutations resulted in a premature stop codon destroying the ligand binding domain of the predictive DAX1 protein.     

Identification of mutations in the GNPTA (MGC4170) gene coding for GlcNAc-phosphotransferase alpha/beta subunits in Korean patients with mucolipidosis type II or type IIIA

Mucolipidosis types II and III are autosomal recessive inherited diseases caused by a deficiency in the lysosomal enzyme N-acetylglucosamine-1 phosphotransferase (GlcNAc-phosphotransferase), which adds phosphate to function as a recognition marker for the uptake and transport of lysosomal enzymes. We investigated mutations in the GNPTA (MGC4170) gene, which codes for the alpha/beta subunits of phosphotransferase, and in the GNPTAG gene, which codes for its gamma subunits in five Korean patients with mucolipidosis type II or IIIA. We identified seven mutations in the GNPTA gene, but none in GNPTAG. The mutations in type II patients included p.Q104X (c.310C>T), p.R1189X (c.3565C>T), p.S1058X (c.3173C>G), p.W894X (c.2681G>A), and p.H1158fsX15 (c.3474_3475delTA), all of which are nonsense or frameshift mutations. However, a splicing site mutation, IVS13+1G>A (c.2715+1G>A) was detected along with a nonsense or a frameshift mutation (p.R1189X or p.E858fsX3 (c.2574_2575delGA)) in two mucolipidosis type IIIA patients. This report shows that mutations in the GNPTA gene coding for the alpha/beta subunits of phosphotransferase, and not mutations in the GNPTAG gene, account for most of the genetic mutations found in Korean patients with mucolipidosis type II or IIIA.     

McArdle disease: the mutation spectrum of PYGM in a large Italian cohort

Deficiency of the muscle isozyme of glycogen phosphorylase is causative of McArdle disease or Glycogen storage disease type V (GSD-V), the most common autosomal recessive disorder of glycogen metabolism. The typical clinical presentation is characterized by exercise intolerance with cramps, and recurrent myoglobinuria. To date, 46 mutations in the PYGM gene have been detected in GSD-V patients. We report the mutational spectrum in 68 Italian patients. We identified 30 different mutations in the PYGM gene, including 19 mutations that have not been reported previously. The novel mutations include: eight missense mutations (c.475G>A, p.G159R; c.689C>G, p.P230R; c.1094C>T, p.A365E; c.1151C>A, p.A384D; c.1182C>T, p.R428C; c.1471C>T, p.R491C; c.2444A>C, p.D815A; c.2477G>C, p.W826S), two nonsense mutations (c.1475G>A, p.W492X; c.1627A>T, p.K543X), five splice site mutations (c.855 +1G>C; c.1092 +1G>A; c. 1093-1G>T; c.1239 +1G>A; c.2380 +1G>A), and four deletions (c.715_717delGTC, p.V239del; c.304delA, p.N102DfsX4; c.1970_2177del, p.V657_G726; c.2113_2114delGG, p.G705RfsX16). Whereas we confirmed lack of direct correlation between the clinical phenotype and the genotype, we also found that the so-called 'common mutation' (p.R50X) accounted for about 43% of alleles in our cohort and that no population-related mutations are clearly identified in Italian patients.     

Identification of seven novel mutations in ABCD1 by a DHPLC-based assay in Italian patients with X-linked adrenoleukodystrophy

We report the molecular findings in 14 patients (12 families) with X-linked adrenoleukodystrophy (X-ALD, MIM# 300100), a well-defined peroxisomal disorder attributed to mutations in the ABCD1 gene on chromosome Xq28. With the aims of determining the spectrum of mutations and developing an efficient molecular genetic test for analysis of at-risk women whose carrier status is unknown, and to offer molecular confirmation of their status to obligate heterozygotes, regardless of their clinical status, we carried out molecular screening by setting up a denaturing high-performance liquid chromatography (DHPLC)-based protocol. We identified eleven hemizygous base changes in ABCD1, including seven new mutations (c.145underscore;146ins4, c.264C>G, c.919C>T, c.994C>T, c.1027G>A, c.1508T>C, and c.1540A>C, resulting in the p.Pro193fs, p.Cys88Trp, p.Gln307X, p.Gln332X, p.Gly343Ser, p.Leu503Pro, and p.Ser514Arg changes, respectively). Adding new variants to the repertoire of ABCD1 mutations in X-ALD, our data provide an efficient, cost-effective, and reliable DHPLC detection protocol for mutation screening of X-ALD families.     

Large-scale population-based metabolic phenotyping of thirteen genetic polymorphisms related to one-carbon metabolism

Several polymorphisms of genes involved in one-carbon metabolism have been identified. The reported metabolic phenotypes are often based on small studies providing inconsistent results. This large-scale study of 10,601 population-based samples was carried out to investigate the association between a panel of biochemical parameters and genetics variants related to one-carbon metabolism. Concentrations of total homocysteine (tHcy), folate, vitamin B(12) (cobalamin), methylmalonic acid (MMA), vitamin B(2) (riboflavin), vitamin B(6) (PLP), choline, betaine, dimethylglycine (DMG), cystathionine, cysteine, methionine, and creatinine were determined in serum/plasma. All subjects were genotyped for 13 common polymorphisms: methylenetetrahydrofolate reductase (MTHFR) c.665C>T (known as 677C>T; p.Ala222Val) and c.1286A>C (known as 1298A>C; p.Glu429Ala); methionine synthase (MTR) c.2756A>G (p.Asp919Gly); methionine synthase reductase (MTRR) c.66A>G (p.Ile22Met); methylenetetrahydrofolate dehydrogenase (MTHFD1) c.1958G>A (p.Arg653Gln); betaine homocysteine methyltransferase (BHMT) c.716G>A (known as 742G>A; p.Arg239Gln); cystathionine beta-synthase (CBS) c.844_845ins68 and c.699C>T (p.Tyr233Tyr); transcobalamin-II (TCN2) c.67A>G (p.Ile23Val) and c.776C>G (p.Pro259Arg); reduced folate carrier-1 (SLC19A1) c.80G>A (p.Arg27His); and paraoxonase-1 (PON1) c.163T>A (p.Leu55Met) and c.575A>G (p.Gln192Arg). The metabolic profile in terms of the measured vitamins and metabolites were investigated for these 13 polymorphisms. We confirmed the strong associations of MTHFR c.665C>T with tHcy and folate, but also observed significant (P<0.01) changes in metabolite concentrations according to other gene polymorphisms. These include MTHFR c.1286A>C (associations with tHcy, folate and betaine), MTR c.2756A>G (tHcy), BHMT c.716G>A (DMG), CBS c.844_845ins68 (tHcy, betaine), CBS c.699C>T (tHcy, betaine, cystathionine) and TCN2 c.776C>G (MMA). No associations were observed for the other polymorphisms investigated.     

Mutation analysis of seven patients with Waardenburg syndrome北大核心CSCD

Objective: To perform genetic analysis for 7 patients with Waardenburg syndrome. Methods: Potential mutation of MITF, PAX3, SOX10 and SNAI2 genes was screened by polymerase chain reaction and direct sequencing. Functions of non-synonymous polymorphisms were predicted with Polyphen2 software. Results: Seven mutations, including c. 649-651delAGA (p. R217del), c. 72delG (p. G24fs), c. 185T>C (p. M62T), c. 118C>T (p. Q40X), c. 422T>C (p. L141P), c. 640C>T (p. R214X) and c. 28G>T (p. G43V), were detected in the patients. Among these, four mutations of the PAX3 gene (c. 72delG, c. 185T>C, c. 118C>T and c. 128G>T) and one SOX10 gene mutation (c. 422T>C) were not reported previously. Three non-synonymous SNPs (c. 185T>C, c. 128G>T and c. 422T>C) were predicted as harmful. Conclusion: Genetic mutations have been detected in all patients with Waardenburg syndrome. © 2016, West China University of Medical Sciences. All rights reserved.     

Novel RS1 mutations associated with X-linked juvenile retinoschisis

To identify mutations in the retinoschisin (RS1) gene in families with X-linked retinoschisis (XLRS). Twenty families with XLRS were enrolled in this study. All six coding exons and adjacent intronic regions of RS1 were amplified by polymerase chain reaction (PCR). The nucleotide sequences of the amplicons were determined by Sanger sequencing. Ten hemizygous mutations in RS1 were detected in patients from 14 of the 20 families. Four of the ten mutations were novel, including c:176G>A (p:Cys59Tyr) in exon?3, c:531T>G (p:Tyr177X), c:607C>G (p:Pro203Ala) and c:668G>A (p:Cys223Tyr) in exon?6. These four novel mutations were not present in 176 normal individuals. The remaining six were recurrent mutations, including c:214G>A (p:Glu72Lys), c:304C>T (p:Arg102Trp), c:436G>A (p:Glu146Lys), c:544C>T (p:Arg182Cys), c:599G>A (p:Arg200His) and c:644A>T (p:Glu215Val). Our study expanded the mutation spectrum of RS1 and enriches our understanding of the molecular basis of XLRS.     

Novel SLC4A11 mutations in patients with recessive congenital hereditary endothelial dystrophy (CHED2). Mutation in brief #958. Online

Autosomal recessive congenital hereditary endothelial dystrophy (CHED2) is a severe and rare corneal disorder that presents at birth or shortly thereafter, characterized by corneal opacification and nystagmus. Recently the gene for CHED2 was identified and seven different mutations in the SLC4A11 gene were reported. Here, we report seven novel mutations and two previously identified mutations in families from India and the United Kingdom with recessive CHED. The novel changes include two nonsense (p.Trp240X; p.Gln800X) three missense (p.Glu143Lys; p.Cys386Arg; p.Arg755Trp) and two splice site mutations (c.2240+1G>A; c.2437-1G>A). Interestingly, the c.2398C>T (p.Gln800X) and c.2437-1G>A identified in two affected siblings represent the first compound heterozygous mutations in the SLC4A11 gene.     

Mutations in EDAR account for one-quarter of non-ED1-related hypohidrotic ectodermal dysplasia

Hypohidrotic ectodermal dysplasia (HED) is characterized by abnormal development of the eccrine sweat glands, hair, and teeth. The X-linked form of the disease, caused by mutations in the ED1 gene, represents the majority of HED cases. Autosomal-dominant and -recessive forms occur occasionally and result from mutations in at least two genes: EDAR and EDARADD. These different forms are phenotypically indistinguishable. To better assess the implication of the EDAR gene in HED, we screened for mutations in 37 unrelated HED families or sporadic cases with no detected mutations in the ED1 gene. We identified 11 different mutations, nine of which are novel variants, in two familial and seven sporadic cases. Seven of the 11 are recessive mutations (c.140G>A (p.Cys47Tyr), c.266G>A (p.Arg89His), c.329A>C (p.Asp110Ala), c.442T>C (p.Cys148Arg), c.1208C>T (p.Thr403Met), c.1302G>T (p.Trp434Cys) and c.528+1G>A), and the other four are probably dominant (c.1129C>T (p.Leu377Phe), c.1237A>C (p.Thr413Pro), c.1253T>C (p.Ile418Thr), and c.1259G>A (p.Arg420Gln)). Our study demonstrates that EDAR is implicated in about 25% of non-ED1 HED, and may account for both autosomal-dominant and -recessive forms. The correlation between the nature and location of EDAR mutations and their mode of inheritance is discussed. A genotype-phenotype relationship was evaluated, since such data could be helpful for genetic counseling.     

Mutations of APC and MYH in unrelated Italian patients with adenomatous polyposis coli

The analysis of APC and MYH mutations in adenomatous polyposis coli patients should provide clues about the genetic heterogeneity of the syndrome in human populations. The entire coding region and intron-exon borders of the APC and MYH genes were analyzed in 60 unrelated Italian adenomatous polyposis coli patients. APC analysis revealed 26 point mutations leading to premature termination, one missense variant and one deletion spanning the entire coding region in 32 unrelated patients. Novel truncating point mutations included c.1176_1177insT (p.His393_PhefsX396), c.1354_1355del (p.Val452_SerfsX458), c.2684C>A (p.Ser895X), c.2711_2712del (p.Arg904_LysfsX910), c.2758_2759del (p.Asp920_CysfsX922), c.4192_4193del (p.Ser1398_SerfsX1407), c.4717G>T (p.Glu1573X) and a novel cryptic APC exon 6 splice site. MYH analysis revealed nine different germline variants in nine patients, of whom five were homozygotes or compound heterozygotes. The mutations included 4 novel MYH missense variants (c.692G>A, p.Arg231His; c.778C>T, p.Arg260Trp; c.1121T>C, p.Leu374Pro; and c.1234C>T, p.Arg412Cys) affecting conserved amino acid residues in the ENDO3c or NUDIX domains of the protein and one novel synonymous change (c.672C>T, p.Asn224Asn). Genotype-phenotype correlations were found in carriers of APC mutations but not in carriers of biallelic MYH mutations, except for a negative correlation with low number of polyps. A distinctive characteristic of patients negative for APC and MYH mutations was a significantly (p<0.0001) older age at diagnosis compared to patients with APC mutations. Moreover, the proportion of cases with an attenuated polyposis phenotype was higher (p = 0.0008) among patients negative for APC and MYH mutations than among carriers of APC or biallelic MYH mutations.     

Identification of the bruton tyrosine kinase (BTK) gene mutations in 20 Australian families with X-linked agammaglobulinemia (XLA)

X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the Bruton tyrosine kinase (BTK) gene. Twenty Australian patients with an XLA phenotype, from 15 unrelated families, were found to have 14 mutations. Five of the mutations were previously described c.83G>A (p.R28H), c.862C>T (p.R288W), c.904G>A (p.R302G), c.1535T>C (p.L512P), c.700C>T (p.Q234X), while nine novel mutations were identified: four missense c.82C>A (p.R28S), c.494G>A (p.C165Y), c.464G>A (p.C155Y), c.1750G>A (p.G584E), one deletion c.142_144delAGAAGA (p.R48_G50del), and four splice site mutations c.241-2A>G, c.839+4A>G, c.1350-2A>G, c.1566+1G>A. Carrier analysis was performed in 10 mothers and 11 female relatives. The results of this study further support the notion that molecular genetic testing represents an important tool for definitive and early diagnosis of XLA and may allow accurate carrier status and prenatal diagnosis.     

Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlations

To better characterize Niemann-Pick type C (NPC) in Spain and improve genetic counselling, molecular analyses were carried out in 40 unrelated Spanish patients. The search identified 70/80 alleles (88%) involving 38 different NPC1 mutations, 26 of which are described for the first time. No patient with NPC2 mutations was identified. The novel NPC1 mutations include 14 amino acid substitutions [R372W (c.1114C>T), P434L (c.1301C>T), C479Y (c.1436G>A), K576R (c.1727G>A), V727F (c.2179G>T), M754K (c.2261T>A), S865L (c.2594C>T), A926T (c.2776G>A), D948H (c.2842G>C), V959E (c.2876T>A), T1036K (c.3107C>A), T1066N (c.3197C>A), N1156I (c.3467A>T) and F1224L (c.3672C>G)], four stop codon [W260X (c.780G>A), S425X (c.1274C>A), C645X (c.1935T>A) and R1059X (c.3175C>T)], two donor splice-site mutations [IVS7+1G>A (g.31432G>A) and IVS21+2insG (g.51871insG)], one in-frame mutation [N961_F966delinsS (c.2882del16bpins1bp)] and five frameshift mutations [V299fsX8 (c.895insT), A558fsX11 (c.1673insG), C778fsX10 (c.2334insT), G993fsX3 (c.2973_78delG) and F1221fsX20 (c.3662delT)]. We also identified three novel changes [V562V (c.1686G>A), A580A (c.1740C>G) and A1187A (c.3561G>T)] in three independent NPC patients and five polymorphisms that have been described previously. The combination of these polymorphisms gave rise to the establishment of different haplotypes. Linkage disequilibrium was detected between mutations C177Y and G993fsX3 and specific haplotypes, suggesting a unique origin for these mutations. In contrast, I1061T mutation showed at least two different origins. The most prevalent mutations in Spanish patients were I1061T, Q775P, C177Y and P1007A (10, 7, 7 and 5% of alleles, respectively). Our data in homozygous patients indicate that the Q775P mutation correlates with a severe infantile neurological form and the C177Y mutation with a late infantile clinical phenotype.     

Misleading findings of homozygosity mapping resulting from three novel mutations in NPHS1 encoding nephrin in a highly inbred community.

PURPOSE: Congenital nephrotic syndrome of the Finnish type (CNF, NPHS1) is a rare autosomal recessive disease caused by mutations in the NPHS1 gene encoding nephrin. We diagnosed congenital nephrotic syndrome in 12 children living in a village near Jerusalem. Most of the inhabitants are descendants of one Muslim family and have maintained their isolation by preference of consanguineous marriages. The aim of this study was to confirm that the NPHS1 gene is responsible for congenital nephrotic syndrome in our population, applying homozygosity mapping. METHODS: DNA samples were genotyped by four microsatellite markers that were in linkage disequilibrium with the NPHS1 gene on chromosome 19q13.1. Immunoperoxidase staining was used to study the expression of nephrin, and mutations were subsequently identified by direct sequencing of the entire coding region of the NPHS1 gene. RESULTS: Haplotype analysis revealed several different haplotypes, leading us to assume erroneously that there was genetic heterogeneity of congenital nephrotic syndrome. Because nephrin was completely absent in kidney tissue of one patient, direct sequencing of all DNA samples was performed, yielding three novel mutations: c.1138C>T (p.Gln380X), c.2160_ 2161insC (p.Cys721fs), and c.1707C>G (p.Ser569Arg). Patients were either homozygous for one of these mutations or compound heterozygotes, and they differed in their phenotype. CONCLUSION: We report the potential pitfalls of performing homozygosity mapping in a highly consanguineous population and discuss the phenomenon of multiple mutations in a given gene within an isolate.     

Identification of novel mutations in classical galactosemia

Classical galactosemia is an autosomal recessive disorder of galactose metabolism due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Treatment through restriction of dietary galactose intake is lifesaving, but, in spite of this diet, most patients develop abnormalities. In this paper we report the mutational spectrum of classical galactosemia in a cohort of 123 Dutch patients, all with biochemically proven classical galactosemia. In the human GALT gene, which is located on chromosome 9p13, we identified 24 different mutations, including nine mutations that have not been reported previously. The novel mutations include five missense mutations (c.152G>A/p.R51Q, c.404C>T/p.S135W, c.687G>T/p.K229N, c.756G>T/p.Q252H, and c.1140A>C/p.X380C), a frame shift mutation (c.410dupT), a splice site mutation (c.821-2A>G), a possible branch point mutation (c.508-29delT), and a large deletion encompassing at least exons 1-11. Six of these novel mutations were found in patients of Dutch descent: p.R51Q, p.S135W, p.K229N, p.Q252H, p.X380C, and c.410dupT.     

Allelic heterogeneity of SMARD1 at the IGHMBP2 locus

Spinal Muscular Atrophy with Respiratory Distress (SMARD) is an autosomal recessive disorder characterized by neurogenic muscular atrophy due to progressive anterior horn cell degeneration and early life-threatening respiratory failure ascribed to diaphragmatic dysfunction. SMARD is clinically and genetically heterogeneous. SMARD type 1 is characterized by onset of respiratory failure within the first weeks of life and has been ascribed to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene on chromosome 11q13-q21. We report here the identification of nine novel IGHMBP2 mutations in five SMARD1 patients, including seven missense [ c.587A>G (p.Gln196Arg), c.647C>T (p.Pro216Leu), c.752T>C (p.Leu251Pro), c.1693G>A (p.Asp565Asn), c.1730T>C (p.Leu577Pro), c.1807C>T (p.Arg603Cys), c.1909C>T (p.Arg637Cys)] and two nonsense mutations [ c.1488C>A (p.Cys496X), c.2368C>T (p.Arg790X)]. Interestingly, 7 of 9 mutations occurred at highly conserved residues of the putative DNA helicase domain. The identification of novel IGHMBP2 variants will hopefully help diagnosing SMARD1 and contribute to a better functional characterization of IGHMBP2 gene product.     

Novel mutations in the TRIM37 gene in Mulibrey Nanism

Mulibrey nanism is an autosomal recessive prenatal-onset growth disorder of unknown pathogenesis. The main clinical features are pre- and postnatal growth failure, characteristic dysmorphic craniofacial features, heart disease, and hepatomegaly. Five truncating mutations in the TRIM37 gene have previously been reported in Mulibrey nanism patients. The TRIM37 protein encodes a novel protein of unknown function. It contains a tripartite motif (TRIM, also denoted the RING-B-box-Coiled-coil or RBCC domain) and a TRAF (tumor necrosis factor-receptor associated factor) domain. TRIM37 localizes to peroxisomes classifying Mulibrey nanism as a peroxisomal disorder. Here we have characterized the genomic structure of the TRIM37 gene, which has 24 exons spanning approximately 109 kb of genomic DNA. Further, we report six novel disease-associated mutations, five of which predict a truncated protein: c.745C>T (p.Gln249X), c.1411C>T (p.Arg471X), c.2056C>T (p.Arg686X), and an 8.6 kb genomic deletion (c.1314+507_1668-207del resulting in p.Arg439fsX4). The sixth mutation (c.965G>T) is the first missense mutation (p.Gly322Val) associated with Mulibrey nanism. It affects the TRAF domain of TRIM37 and results in altered subcellular localization of the mutant TRIM37 protein, further suggesting that it is pathogenic.     

P gene mutations associated with oculocutaneous albinism type II (OCA2)

Oculocutaneous albinism type II (OCA2) is the most common form of albinism in humans. OCA2 has been previously associated with mutations of the P gene, the human homologue to the murine pink-eyed dilution gene. The P gene encodes a 110 kDa protein containing 12 potential membrane spanning domains and is associated with melanosomal membranes. The specific function of the P protein is currently unknown but is thought to be involved in tyrosinase processing and transport. We report nine novel mutations in the P gene associated with OCA2. These include two missense mutations, c.1938A>C (p.Ile646Val) and c.1556T>C (p.Val519Ala); one nonsense mutation c.612G>A (p.Trp204X); five frameshift mutations: c.2372_2373delTC, c.1555delG, c.1938_1939insC, c.2050delT, and c.1045_1046delAT; and a splice site mutation c.1951+1G>A. We also report 12 novel polymorphisms including one amino acid substitution, c.2365_2366GC>CA (p.Ala789Glu). At present, there is no functional assay to determine if a mutation is truly pathogenic. The presence of numerous polymorphisms of the P gene in the coding region, several of which result in amino acid substitutions, makes molecular diagnosis problematic. To ensure accurate molecular diagnosis, further mutational analysis will be necessary to produce a comprehensive list of mutations associated with OCA2. This information will also help define the critical functional domains of the P protein. Mutations associated with OCA2 can be found in the Albinism Database (http://albinismdb.med.umn.edu).