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

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 melanosomal 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. © 1998 Wiley-Liss, Inc.     

Mutations of the human P gene associated with Type II oculocutaneous albinism (OCA2). Mutations in brief no. 205. Online

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.     

Identification of P gene mutations in individuals with oculocutaneous albinism in sub-Saharan Africa

Oculocutaneous albinism (OCA) is an inherited disorder resulting in hypopigmentation of the skin, hair, and eyes. OCA type 2 (tyrosinase-positive) is the most common recessively inherited disorder among southern African Blacks. OCA2 is also seen in southern African Caucasoids, but is less frequent. The gene responsible for this type of albinism, P, is the human homolog of the mouse pink-eyed dilution gene. Mutations at this locus are also responsible for the milder hypopigmentation phenotype seen in individuals with brown oculocutaneous albinism (BOCA). A common African P mutation was identified in Black OCA2 individuals, and has since been shown to occur in Black individuals with brown OCA as well. This mutation is a 2.7 kb interstitial deletion. In this study, we undertook to screen the coding region of the P gene for mutations in the non-2.7 kb deletion alleles of OCA2 patients who did not carry the deletion allele in either one or both of their P genes. We identified four mutations (A334V, 614delA, 683insG [corrected], 727insG) in a group of 39 unrelated Black OCA2 patients with a total of 52 non-2.7 kb deletion OCA2 genes. When taking all OCA2 cases into consideration, including those homozygous for the 2.7 kb deletion mutation, these account for a further 1.7% of OCA2 mutations in southern African Blacks, increasing the overall mutation detection rate to 78.7%. Three mutations (E678K, L688F, I370T) were identified in a group of 15 Black patients with an initially unclassified type of OCA and another three mutations (IVS 14-2 (a-->g), V350M, P743L) were identified in nine Caucasoid OCA patients. Relatively few mutations, all with low frequency, were identified in the non-2.7 kb deletion OCA genes. We propose that other mutations may lie either within intronic sequence or within the promoter region of the gene.     

DNA-based prenatal diagnosis of a Korean family with tyrosinase-related oculocutaneous albinism (OCA1)

Summary Tyrosinase-related oculocutaneous albinism (OCA1), an autosomal recessive inborn error of pigmentation, is caused by the deficiency of tyrosinase. We had previously identified two different mutations of theTYR gene in a four year old Korean male with mild OCA; a P310insC frameshift in exon 2 and an IVS2-7t→a, -10--11deltt splice junction mutation in exon 3. Here we report a prenatal diagnostic study of a subsequent fetus of the above family that was at 25% risk of OCA1. SSCP/heteroduplex screening, restriction enzyme digestion, and allele-specific oligonucleotide hybridization analyses of DNA obtained by chorionic villus sampling indicated that the fetus was a compound heterozygote for the paternal P310insC and the maternal IVS2-7t→a, -10--11deltt mutations. The diagnosis was later confirmed by observation of poorly pigmented irides of the abortus terminated at the 18th week of gestation. This approach provides a fast and reliable method for DNA-based prenatal diagnosis when specific mutations are known in families at high risk of OCA1.     

Tyrosinase gene mutations in type I (tyrosinase-deficient) oculocutaneous albinism define two clusters of missense substitutions

Type I (tyrosinase-deficient) oculocutaneous albinism (OCA) results from mutations of the gene encoding tyrosinase, the enzyme that catalyzes the first 2 steps of melanin pigment biosynthesis. In type IA (tyrosinase-negative) OCA tyrosinase enzymatic activity is completely absent, and in type IB (“yellow”) OCA tyrosinase activity is greatly reduced. Here, we describe 11 novel mutations of the tyrosinase gene in Caucasian patients with these 2 forms of type I OCA. Type I OCA in Caucasians appears to result from a great variety of different uncommon alleles. More than 80% of the known missense substitutions associated with type I OCA cluster within 2 relatively small regions of the tyrosinase polypeptide, suggesting that these may correspond to functionally important sites within the enzyme. © 1992 Wiley-Liss, Inc.     

Tyrosinase gene mutations in type I (tyrosinase-deficient) oculocutaneous albinism define two clusters of missense substitutions.

Type I (tyrosinase-deficient) oculocutaneous albinism (OCA) results from mutations of the gene encoding tyrosinase, the enzyme that catalyzes the first 2 steps of melanin pigment biosynthesis. In type IA (tyrosinase-negative) OCA tyrosinase enzymatic activity is completely absent, and in type IB ("yellow") OCA tyrosinase activity is greatly reduced. Here, we describe 11 novel mutations of the tyrosinase gene in Caucasian patients with these 2 forms of type I OCA. Type I OCA in Caucasians appears to result from a great variety of different uncommon alleles. More than 80% of the known missense substitutions associated with type I OCA cluster within 2 relatively small regions of the tyrosinase polypeptide, suggesting that these may correspond to functionally important sites within the enzyme.     

眼皮肤白化病Ⅰ型产前基因诊断

目的对已生育过眼皮肤白化病Ⅰ型（oculocutaneous albinism type Ⅰ，OCA1）患儿的两个家系进行酪氨酸酶（tyrosinase，TYR）基因TYR的突变研究和产前基因诊断。方法应用PCR技术扩增TYR基因各外显子、外显子．内含子交界区及启动子区，直接以DNA序列测定技术分析先证者或其父母的基因突变，明确致病性突变后，检测胎儿TYR基因相应位点的DNA序列，获知胎儿的基因型。结果家系1的先证者为R278X和929insC突变复合杂合子；胎儿未获得这2种突变等位基因，基因型和表型均正常。家系2先证者的父母分别为IVS4＋3A→T和G253E突变的杂合子，胎儿只获得了父源性的IVS4＋3A→T突变等位基因，未获得母源性G253E突变等位基因，胎儿为表型正常的致病基因携带者。结论此为中国大陆首次真正意义上的OCA1产前基因诊断；应用上述基因分析方法进行OCA1产前基因诊断是可行的。     

Mutations of the human tyrosinase gene associated with tyrosinase related oculocutaneous albinism (OCA1). Mutations in brief no. 204. Online

Mutations in the human tyrosinase gene produce tyrosinase-related oculocutaneous albinism (OCA1, MIM #203100). Tyrosinase is a copper containing enzyme and is responsible for catalyzing the rate limiting step in melanin biosynthesis, the hydroxylation of tyrosine to dopaquinone. We report 13 new mutations in the tyrosinase gene associated with OCA1A (without pigment) and OCA1B (with pigment) including 9 missense mutations (H19Q, R521, R77C, G97R, C289R, L312V, P313R, F340L and H404P), two nonsense mutations (W80X and R116X) and two frameshift mutations (53delG and 223 delG). Our previous work has defined clusters of missense mutations that appear to represent functional domains of the enzyme, and three of the missense mutations fall into these clusters including two (F340L and H404P) that flank the copper B bindng site and the missense mutation R52I that is located in the amino terminal end cluster of the protein. The G97R missense mutation is the first identified within the epidermal growth factor (EGF)-like sequence and the H19Q missense mutation alters the cleavage site of the signal peptide sequence. Mutational analysis can provide a definitive diagnosis of the type of OCA as well as help structure/function analysis.     

一个近亲婚配家系中的一种P基因新突变

目的在DNA水平上对1个有2例患者的姨表兄妹近亲婚配家系中的眼皮肤白化病患者进行分型诊断。方法用PCR扩增先证者P基因及TYR基因各外显子、外显子-内含子交界区及3＇端和5＇端非翻译区，以DNA序列测定技术检测基因突变，以DNA测序技术和限制性内切酶酶切法检测该家系其他成员及群体中正常人的相应基因位点。结果先证者和其白化病妹妹为P基因A787T突变纯合子，其父母和表型正常的弟弟均为A787T突变杂合子。先证者TYR基因未见突变。群体中102名表型正常者中无A787T突变等位基因。结论在基因水平确定我国存在眼皮肤白化病Ⅱ型，同时发现了一种P基因病理性新突变。     

三例眼皮肤白化病患者TYR和P基因的突变分析

目的 分析眼皮肤白化病(oculocutaneom albinism,OCA)患者酪氨酸酶(tyrosinase,TYR)基因和P基因的基因突变.方法 应用聚合酶链反应(polymerase chain reaction ,PCR)和变性高效液相色谱(de-naturing high-perfomanee liquia chromatography,DHPLC)技术对3例患者的眼皮肤白化病Ⅰ、Ⅱ型相关基因(TYR和P基因)的外显子进行突变检测,并对DHPLC检出的突变样本进行测序和限制性内切酶分析以验证该突变.针对未见报道的新突变,筛查100名表型正常的无关个体,排除多态的可能.结果 在3例患者中检测出两种P基因突变,未检测到TYR基因突变.其中,患者1的P基因第13外显子发生杂合突变T450M;患者2的P基因发生两个杂合突变,分别是第13外显子T450M和第23外显子G775R;患者3的P基因第23外显子发生杂合突变G775R.P基因第13外显子限制性内切酶分析显示,患者1、2均出现杂合突变T450M导致的Oli I酶切位点部分消失,100名表型正常的无关个体未检出该突变;经检索,T450M为一未见报道的新突变.结论 联合应用PCR、DHPLC、DNA测序和限制性内切酶分析的方法可有效的对白化病进行基因诊断.     

Insertion/deletion mutations of type I oculocutaneous albinism in chinese patients from Taiwan

Type I oculocutaneous albinism (OCA1) is an autosomal recessive disorder, which is caused by the reduction or the absence of tyrosinase activity in melanocytes of the skin, hair and eyes. Although tyrosinase mutations of OCA1 have been extensively analyzed in most populations worldwide, there is no systemic study of OCA1 mutation in Chinese patients. By use of single strand conformation polymorphism and direct sequencing, we had detected 21 mutant alleles out of 24 OCA1 chromosomes screened (87.5%). Detected mutant alleles include one splicing site, three insertion/deletion and five missense mutations, of which the splicing site nucleotide alteration (IVS 1-3C>G) and two each of the insertion/deletion (232-233 ins GGG and 861-862 del TT) and missense mutations (Cys 289 Gly and Trp 400 Leu) are novel. The ins/del mutations accounts for about 37.5% in Chinese OCA1 alleles. The 232-233 ins GGG, one of the novel mutations, was found to be most frequent (25%) among the OCA1 alleles in Chinese. Through this study, we found that while some of the OCA mutant alleles were identified in other populations, ethnic difference still exists. Hum Mutat 14:542, 1999.     

A nonsense mutation in the tyrosinase gene of Afghan patients with tyrosinase negative (type IA) oculocutaneous albinism.

We detected a nonsense mutation in the tyrosinase gene of two Afghan sibs with classical tyrosinase negative (type IA) oculocutaneous albinism. The mutation, a single base substitution at codon 178, creates an amber termination codon that truncates the 529 amino acid tyrosinase polypeptide at this position. The patients' parents are first cousins, and the patients are therefore homoallelic for this mutation.     

Oculocutaneous albinism type 2 (OCA2) with homozygous 2.7-kb deletion of the P gene and sickle cell disease in a Cameroonian family. Identification of a common TAG haplotype in the mutated P gene

In this study, we report on a Cameroonian family from the Ewondo ethnic group, presenting with three oculocutaneous albinism type 2 (OCA2) patients homozygous for the 2.7-kb deletion of the P gene. In one of these patients OCA2 was associated with sickle cell anaemia and in two with the sickle cell trait. We took this opportunity to determine single nucleotide polymorphism (SNP) haplotypes within the P gene in this family in comparison with a group of 53 OCA2 patients homozygous for the same mutation and with a matched unrelated full-coloured control group of 49 subjects, originating from seven different ethnic groups of Southern Cameroon including Ewondo. A combination of five exonic and intronic SNPs in the OCA2 gene was genotyped by sequencing PCR products. We found 3 different haplotypes (TAGCT, TAGTT and TAGCC with frequencies of 0.66, 0.28 and 0.06, respectively) associated with the mutation in the 53 OCA2 patients, while 11 different haplotypes were observed in the control group. These observations suggest that the mutation appeared on the relatively frequent haplotype TAGCT, and that the two other haplotypes are derived from two independent recombination events. These haplotypic data, associated with a value of 1/15,000 for the prevalence of the 2.7-kb mutation, a present effective population size of 10,000,000 for Cameroon and a recombination rate of 0.0031, allowed us to estimate that this mutation originated 4,100–5,645 years ago.     

Minimal pigment: a new type of oculocutaneous albinism

Minimal pigment, a new type of oculocutaneous albinism (OCA), is described. At birth, affected individuals had no skin or eye pigment, and white hair and blue irides, but minimal amounts of pigment developed in the iris during the first decade of life. They had no measurable hairbulb tyrosinase activity. A characteristic and unusual pattern of parental activity was found in each of three families studied, with one parent having normal and the other parent having abnormally low tyrosinase activity. The melanocyte ultrastructure was normal and variations in premelanosomal pigmentation correlated with tyrosinase activity. This clinical and biochemical pattern has not been seen in any of the previously described types of OCA. The biochemical defect in minimal pigment OCA is unknown.     

眼皮肤白化病Ⅳ型基因MATP的SNPs与皮肤颜色

皮肤颜色差异是人类生物学中最易见、区分不同人群的差异之一,这种差异来自自然的选择,有几个候选基因可以解释其中差异,其中眼皮肤白化病Ⅳ型基因MATP就是其中之一。眼皮肤白化病Ⅳ型基因MATP至今已发现有11种单核苷酸多态性（SNPs）,这些SNPs中有些与皮肤颜色有显著相关,如p.Phe374Leu。