Rufous oculocutaneous albinism in southern African Blacks is caused by mutations in the TYRP1 gene.

Oculocutaneous albinism (OCA) is the most common autosomal recessive disorder among southern African Blacks. There are three forms that account for almost all OCA types in this region. Tyrosinase-positive OCA (OCA2), which is the most common, affects approximately 1/3,900 newborns and has a carrier frequency of approximately 1/33. It is caused by mutations in the P gene on chromosome 15. Brown OCA (BOCA) and rufous OCA (ROCA) account for the majority of the remaining phenotypes. The prevalence of BOCA is unknown, but for ROCA it is approximately 1/8,500. Linkage analysis performed on nine ROCA families showed that ROCA was linked to an intragenic marker at the TYRP1 locus (maximum LOD score = 3.80 at straight theta=.00). Mutation analysis of 19 unrelated ROCA individuals revealed a nonsense mutation at codon 166 (S166X) in 17 (45%) of 38 ROCA chromosomes, and a second mutation (368delA) was found in an additional 19 (50%) of 38 chromosomes; mutations were not identified in the remaining 2 ROCA chromosomes. In one family, two siblings with a phenotypically unclassified form of albinism were found to be compound heterozygotes for mutations (S166X/368delA) at the TYRP1 locus and were heterozygous for a common 2.7-kb deletion in the P gene. These findings have highlighted the influence of genetic background on phenotype, in which the genotype at one locus can be influenced by the genotype at a second locus, leading to a modified phenotype. ROCA, which in southern African Blacks is caused by mutations in the TYRP1 gene, therefore should be referred to as "OCA3," since this is the third locus that has been shown to cause an OCA phenotype in humans.     

The tyrosinase-positive oculocutaneous albinism gene shows locus homogeneity on chromosome 15q11-q13 and evidence of multiple mutations in southern African negroids.

Tyrosinase-positive oculocutaneous albinism (ty-pos OCA) is an autosomal recessive disorder of the melanin pigmentary system. South African ty-pos OCA individuals occur with two distinct phenotypes, with or without darkly pigmented patches (ephelides, or dendritic freckles) on exposed areas of the skin. These phenotypes are concordant within families, suggesting that there may be more than one mutation at the ty-pos OCA locus. Linkage studies carried out in 41 families have shown linkage between markers in the Prader-Willi/Angelman syndrome (PWS/AS) region on chromosome 15q11-q13 and ty-pos OCA. Analysis showed no obligatory crossovers between the alleles at the D15S12 locus and ty-pos OCA, suggesting that the D15S12 locus is very close to or part of the disease locus, which is postulated to be the human homologue, P, of the mouse pink-eyed dilution gene, p. Unlike caucasoid "ty-pos OCA" individuals, negroid ty-pos OCA individuals do not show any evidence of locus heterogeneity. Studies of allelic association between the polymorphic alleles detected at the D15S12 locus and ephelus status suggest that there was a single major mutation giving rise to ty-pos OCA without ephelides. There may, however, be two major mutations causing ty-pos OCA with ephelides, one associated with D15S12 allele 1 and the other associated with D15S12 allele 2. The two loci, GABRA5 and D15S24, flanking D15S12, are both hypervariable, and many different haplotypes were observed with the alleles at the three loci on both ty-pos OCA-associated chromosomes and "normal" chromosomes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Type 2 oculocutaneous albinism (OCA2) in Zimbabwe and Cameroon: distribution of the 2.7-kb deletion allele of the P gene

In previous studies, we characterized a 2.7-kb interstitial deletion allele of the P gene associated with tyrosinase-positive oculocutaneous albinism (OCA2) in African Americans and Africans. In this study, we investigated the frequency of this allele among OCA2 subjects in two African countries, Zimbabwe and Cameroon. The deletion allele was most common in Zimbabwe, comprising nearly all (92%) mutant alleles, which is the highest incidence reported so far. In addition, the deletion allele was widespread but less common among OCA2 Cameroonians and accounted for 65% of the mutant alleles. Received: 20 March 1997 / Accepted: 8 May 1997     

An intragenic deletion of the P gene is the common mutation causing tyrosinase-positive oculocutaneous albinism in southern African Negroids.

Tyrosinase-positive oculocutaneous albinism (OCA2), an autosomal recessive disorder of the melanin biosynthetic pathway, is the most common recessive disorder occurring in southern African Bantu-speaking Negroids, with an overall prevalence of 1/3,900. The OCA2 gene, P, has been mapped to chromosome 15q11-q13, and recently alterations in the P gene have been identified in OCA2 individuals. An intragenic deletion has been described and proposed to be of African origin because of its occurrence in four unrelated African American OCA2 individuals and in two individuals, one from Zaire and the other from Cameroon. This study shows that the intragenic deletion is a common cause of OCA2 in southern African Negroids (114/146 [.78]; OCA2 chromosomes) and is associated with one common haplotype (43/55 [.78]; OCA2 chromosomes), confirming the African origin of this allele. On the basis of haplotype data, it would appear that at least seven additional, less frequent OCA2 mutations occur in this population.     

MC1R mutations modify the classic phenotype of oculocutaneous albinism type 2 (OCA2)

The heterogeneous group of disorders known as oculocutaneous albinism (OCA) shares cutaneous and ocular hypopigmentation associated with common developmental abnormalities of the eye. Mutations of at least 11 loci produce this phenotype. The majority of affected individuals develop some cutaneous melanin; this is predominantly seen as yellow/blond hair, whereas fewer have brown hair. The OCA phenotype is dependent on the constitutional pigmentation background of the family, with more OCA pigmentation found in families with darker constitutional pigmentation, which indicates that other genes may modify the OCA phenotype. Sequence variation in the melanocortin-1 receptor (MC1R) gene is associated with red hair in the normal population, but red hair is unusual in OCA. We identified eight probands with OCA who had red hair at birth. Mutations in the P gene were responsible for classic phenotype of oculocutaneous albinism type 2 (OCA2) in all eight, and mutations in the MC1R gene were responsible for the red (rather than yellow/blond) hair in the six of eight who continued to have red hair after birth. This is the first demonstration of a gene modifying the OCA phenotype in humans.     

A frequent tyrosinase gene mutation associated with type I-A (tyrosinase-negative) oculocutaneous albinism in Puerto Rico.

We have determined the mutations in the tyrosinase gene from 12 unrelated Puerto Rican individuals who have type I-A (tyrosinase-negative) oculocutaneous albinism (OCA). All but one individual are of Hispanic descent. Nine individuals were homozygous for a missense mutation (G47D) in exon I at codon 47. Two individuals were heterozygous for the G47D mutation, with one having a missense mutation at codon 373 (T373K) in the homologous allele and the other having an undetermined mutation in the homologous allele. One individual with negroid features was homozygous for a nonsense mutation (W236X). The population migration between Puerto Rico and the Canary Islands is well recognized. Analysis of three individuals with OCA from the Canary Islands showed that one was a compound heterozygote for the G47D mutation and for a novel missense mutation (L216M), one was homozygous for a missense mutation (P81L), and one was heterozygous for the missense mutation P81L. The G47D and P81L missense mutations have been previously described in extended families in the United States. Haplotypes were determined using four polymorphisms linked to the tyrosinase locus. Haplotype analysis showed that the G47D mutation occurred on a single haplotype, consistent with a common founder for all individuals having this mutation. Two different haplotypes were found associated with the P81L mutation, suggesting that this may be either a recurring mutation for the tyrosinase gene or a recombination between haplotypes.     

Mutations of the tyrosinase gene in patients with oculocutaneous albinism from various ethnic groups in Israel.

We have analyzed the tyrosinase (TYR) gene in 38 unrelated patients with oculocutaneous albinism (OCA), derived from several different ethnic groups of the diverse population of Israel. We detected TYR gene mutations in 23 of the 34 patients with apparent type I (i.e., tyrosinase-deficient) OCA and in none of the patients with other clinical forms of albinism. Among Moroccan Jews with type IA (i.e., tyrosinase-negative) OCA, we detected a highly predominant mutant allele containing a missense substitution, Gly47Asp (G47D). This mutation occurs on the same haplotype as in patients from the Canary Islands and Puerto Rico, suggesting that the G47D mutation in these ethnically distinct populations may stem from a common origin.     

The tyrosinase-positive oculocutaneous albinism locus maps to chromosome 15q11.2-q12.

Tyrosinase-positive oculocutaneous albinism (ty-pos OCA), an autosomal recessive disorder of the melanin biosynthetic pathway, is the most common type of albinism occurring worldwide. In southern African Bantu-speaking negroids it has an overall prevalence of about 1/3,900. Since the basic biochemical defect is unknown, a linkage study with candidate loci, candidate chromosomal regions, and random loci was undertaken. The ty-pos OCA locus was found to be linked to two arbitrary loci, D15S10 and D15S13, in the Prader-Willi/Angelman chromosomal region on chromosome 15q11.2-q12. The pink-eyed dilute locus, p, on mouse chromosome 7, maps close to a region of homology on human chromosome 15q, and we postulate that the ty-pos OCA and p loci are homologous.     

Variation in the tyrosinase gene associated with a white humpback whale (Megaptera novaeangliae)

Tyrosinase-negative oculocutaneous albinism (OCA1A) is characterized by lifelong white hair and skin, a phenotype that has been described in most mammalian species worldwide. Tyrosinase is the key enzyme in melanin biosynthesis, and mutations in the tyrosinase gene result in OCA1A. We examined sequence variation at exon 1 of the tyrosinase gene in 66 humpback whale samples collected from the east coast of Australia, including an anomalously white humpback whale known as "Migaloo." We identified 3 novel variants, including a cytosine deletion that results in a premature stop codon in exon 1. The deletion truncates the tyrosinase protein including the putative catalytic domains that are essential for tyrosinase enzymatic activity. Migaloo was homozygous for this deletion, suggesting that the albino phenotype is a consequence of inactive tyrosinase caused by the frameshift in the tyrosinase gene.     

Oculocutaneous albinism (OCA2) in sub-Saharan Africa: distribution of the common 2.7-kb P gene deletion mutation

Oculocutaneous albinism (OCA2) is the most common autosomal recessive disorder in the South African Negroid population, occurring with a prevalence of 1/3900 individuals. The OCA2 locus, P, has been mapped to chromosome 15q11–q13 and a 2.7-kb interstitial deletion has been found to be the common mutation in Africa. This study reports the detection of the deletion allele in OCA2-affected individuals from the southern African, Zambian and Central African Republic (CAR) Negroid populations (0.77, 131/170 OCA2 chromosomes; 0.79, 11/14; 0.33, 4/12, respectively). Normally pigmented individuals from different African countries were also tested. The deletion mutation was found at a frequency of 0.013 (10/780) in the normally pigmented southern African Negroid population and at a lower frequency in individuals from central Africa (0.002; 2/834), including individuals from Zambia, Cameroon, Zaire and the CAR. The study confirms the African origin of this deletion allele. Haplotype analysis suggests that the deletion mutation probably occurred only once and that it arose before the divergence of these African populations, which is estimated to be about 2000– 3000 years ago. The unusually high frequency of OCA2 mutations, in particular the 2.7-kb deletion, suggests some selective agent or genetic drift. Received: 24 September 1996 / Revised: 8 November 1996     

Mutational Analysis of the TYR and OCA2 Genes in Four Chinese Families with Oculocutaneous Albinism

Background

Oculocutaneous albinism (OCA) is an autosomal recessive disorder. The most common type OCA1 and OCA2 are caused by homozygous or compound heterozygous mutations in the tyrosinase gene (TYR) and OCA2 gene, respectively.

Objective

The purpose of this study was to evaluate the molecular basis of oculocutaneous albinism in four Chinese families.

Patients and Methods

Four non-consanguineous OCA families were included in the study. The TYR and OCA2 genes of all individuals were amplified by polymerase chain reaction (PCR), sequenced and compared with a reference database.

Results

Four patients with a diagnosis of oculocutaneous albinism, presented with milky skin, white or light brown hair and nystagmus. Genetic analyses demonstrated that patient A was compound heterozygous for c.1037-7T.A, c.1037-10_11delTT and c.1114delG mutations in the TYR gene; patient B was heterozygous for c.593C>T and c.1426A>G mutations in the OCA2 gene, patients C and D were compound heterozygous mutations in the TYR gene (c.549_550delGT and c.896G>A, c.832C>T and c.985T>C, respectively). The heterozygous c.549_550delGT and c.1114delG alleles in the TYR gene were two novel mutations. Interestingly, heterozygous members in these pedigrees who carried c.1114delG mutations in the TYR gene or c.1426A>G mutations in the OCA2 gene presented with blond or brown hair and pale skin, but no ocular disorders when they were born; the skin of these patients accumulated pigment over time and with sun exposure.

Conclusion

This study expands the mutation spectrum of oculocutaneous albinism. It is the first time, to the best of our knowledge, to report that c.549_550delGT and c.1114delG mutations in the TYR gene were associated with OCA. The two mutations (c.1114delG in the TYR gene and c.1426A>G in the OCA2 gene) may be responsible for partial clinical manifestations of OCA.     

Mutation profile of all 49 exons of the human myosin VIIA gene,and haplotype analysis,in Usher 1B families from diverse origins.

Usher syndrome types I (USH1A-USH1E) are a group of autosomal recessive diseases characterized by profound congenital hearing loss, vestibular areflexia, and progressive visual loss due to retinitis pigmentosa. The human myosin VIIA gene, located on 11q14, has been shown to be responsible for Usher syndrome type 1B (USH1B). Haplotypes were constructed in 28 USH1 families by use of the following polymorphic markers spanning the USH1B locus: D11S787, D11S527, D11S1789, D11S906, D11S4186, and OMP. Affected individuals and members of their families from 12 different ethnic origins were screened for the presence of mutations in all 49 exons of the myosin VIIA gene. In 15 families myosin VIIA mutations were detected, verifying their classification as USH1B. All these mutations are novel, including three missense mutations, one premature stop codon, two splicing mutations, one frameshift, and one deletion of >2 kb comprising exons 47 and 48, a part of exon 49, and the introns between them. Three mutations were shared by more than one family, consistent with haplotype similarities. Altogether, 16 USH1B haplotypes were observed in the 15 families; most haplotypes were population specific. Several exonic and intronic polymorphisms were also detected. None of the 20 known USH1B mutations reported so far in other world populations were identified in our families.     

Oculocutaneous albinism with TYRP1 gene mutations in a Caucasian patient

Non-syndromic oculocutaneous albinism (OCA) is a clinically and genetically heterogeneous autosomal recessive disorder with mutations identified in several genes: OCA1 (tyrosinase, TYR), OCA2 (OCA2), OCA3 (tyrosinase-related protein 1, TYRP1), and OCA4 (membrane-associated transporter protein, MATP). OCA3 was thought to be restricted to black populations, where it was clinically described as rufous or brown albinism, until the recent report of a homozygous TYRP1 mutation in Caucasian patients from a consanguineous Pakistani family. Here, we describe a German patient of Caucasian origin, with a light-yellow skin, yellow-gold hair with orange highlights, fair eyelashes, several pigmented naevi, and no tendency to tan, only to burn. Eye-colour is blue-green with substance defects of the iris. Molecular analysis did not reveal any mutation in the TYR and OCA2 genes. Two mutations were found in the TYRP1 gene: a missense mutation (c.1066G>A/p.Arg356Glu) that was inherited from the mother, and a de novo single-base deletion (c.106delT/p.Leu36X). This finding suggests that mutation screening should be extended to the TYRP1 gene in patients from all ethnic origins, at least in cases where no mutations have been identified in the other OCA genes.     

Genetic mapping of the dominant albino locus in rainbow trout (Oncorhynchus mykiss)

Albinism in animals is generally a recessive trait, but in Japan a dominant oculocutaneous albino (OCA) mutant strain has been isolated in rainbow trout (Oncorhyncus mykiss). After confirming that this trait is not due to a tyrosinase gene mutation that causes OCA1 (tyrosinase-negative OCA), we combined the amplified fragment length polymorphism (AFLP) technique with bulked segregant analysis (BSA) to map the gene involved in dominant oculocutaneous albinism. Four AFLP markers tightly linked to the dominant albino locus were identified. One of these markers was codominant and we have it converted into a GGAGT-repeat microsatellite marker, OmyD-AlbnTUF. Using this pentanucleotide-repeat DNA marker, the dominant albino locus has been mapped on linkage group G of a reference linkage map of rainbow trout. The markers identified here will facilitate cloning of the dominant albino gene in rainbow trout and contribute to a better understanding of tyrosinase-negative OCA in animals.     

Increasing the complexity: new genes and new types of albinism

Albinism is a rare genetic condition globally characterized by a number of specific deficits in the visual system, resulting in poor vision, in association with a variable hypopigmentation phenotype. This lack or reduction in pigment might affect the eyes, skin, and hair (oculocutaneous albinism, OCA), or only the eyes (ocular albinism, OA). In addition, there are several syndromic forms of albinism (e.g. Hermansky–Pudlak and Chediak–Higashi syndromes, HPS and CHS, respectively) in which the described hypopigmented and visual phenotypes coexist with more severe pathological alterations. Recently, a locus has been mapped to the 4q24 human chromosomal region and thus represents an additional genetic cause of OCA, termed OCA5, while the gene is eventually identified. In addition, two new genes have been identified as causing OCA when mutated: SLC24A5 and C10orf11, and hence designated as OCA6 and OCA7, respectively. This consensus review, involving all laboratories that have reported these new genes, aims to update and agree upon the current gene nomenclature and types of albinism, while providing additional insights from the function of these new genes in pigment cells.     

A single base deletion in the SLC45A2 gene in a Bullmastiff with oculocutaneous albinism

Oculocutaneous albinism type 4 (OCA4) in humans and similar phenotypes in many animal species are caused by variants in the SLC45A2 gene, encoding a putative sugar transporter. In dog, two independent SLC45A2 variants are known that cause oculocutaneous albinism in Doberman Pinschers and several small dog breeds respectively. For the present study, we investigated a Bullmastiff with oculocutaneous albinism. The affected dog was highly inbred and resulted from the mating of a sire to its own grandmother. We obtained whole genome sequence data from the affected dog and searched specifically for variants in candidate genes known to cause albinism. We detected a single base deletion in exon 6 of the SLC45A2 gene (NM_001037947.1:c.1287delC) that has not been reported thus far. This deletion is predicted to result in an early premature stop codon. It was confirmed by Sanger sequencing and perfectly co‐segregated with the phenotype in the available family members. We genotyped 174 unrelated dogs from diverse breeds, all of which were homozygous wildtype. We therefore suggest that SLC45A2:c.1287delC causes the observed oculocutaneous albinism in the affected Bullmastiff.     

Human oculocutaneous albinism caused by single base insertion in the tyrosinase gene

Tyrosinase-negative oculocutaneous albinism (OCA) is an inborn error of metabolism, characterized by a complete lack of melanin pigments in the eyes and skin. We have isolated and characterized the tyrosinase gene of one affected child (S.S.) with tyrosinase-negative OCA. Sequence analysis reveals a single-base insertion in the exon 2 that shifts the reading frame and introduces a premature termination signal (TGA codon) after the amino acid residue 298. Functional analysis of the mutated gene indicates that such a truncated tyrosinase lacking one potential copper-binding region is catalytically inactive. We therefore conclude that the albino phenotype of the patient S.S. is a consequence of the inactive tyrosinase caused by the nonsense mutation in the tyrosinase gene.     

Novel and recurrent mutations in the tyrosinase gene and the P gene in the German albino population

Albinism is a heterogeneous group of genetic disorders resulting from deficiencies in pigmentation. Clinically, it is divided into ocular (OA) and oculocutaneous albinism (OCA). OCA involves lack of pigment in the skin, hair, and eyes and results from mutations in the tyrosinase gene or in the P gene. OA mainly affects pigmentation in the visual system and may be a mild form of OCA or may be caused by other genetic defects. Clinical diagnosis of albinism type is difficult, because of the observed range of phenotypic variation. Thus, genetic analysis may be helpful with respect to a more accurate diagnosis. Here, we report the mutational profile, determined by genetic analysis of the tyrosinase and P genes, of a large German albino population. We have revealed a total of 42 distinct mutations, 19 of which are novel. Of the 74 unrelated patients screened, 32 (43%) had mutations in the tyrosinase gene, 16 (22%) had P gene mutations, and 26 (35%) patients had no detectable genetic abnormalities. This defines a population of albino patients who are tyrosinase-gene- and P-gene-negative and who thus may represent a good study group for searching for additional genes associated with albinism.     

Frequent intragenic deletion of the P gene in Tanzanian patients with type II oculocutaneous albinism (OCA2).

Type II oculocutaneous albinism (OCA2) is an autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in the skin, hair, and eyes. OCA2, which results from mutations of the P gene, is the most frequent type of albinism in African and African-American patients. OCA2 is especially frequent in Tanzania, where it occurs with an incidence of approximately 1/1,400. We have identified abnormalities of the P gene in each of 13 unrelated patients with OCA2 from Tanzania. One of these, a deletion of exon 7, is strongly predominant, accounting for approximately 77% of mutant alleles in this group of patients.