Oculocutaneous albinism type 1: the last 100 years

Research on human albinism has been central to many of the major discoveries in human genetics. These include the first evidence that Mendel's rules of genetic segregation apply to humans, first published in 1903. Contrary to initial thought that albinism is caused by mutations in a single gene, we now know that the genetics of albinism are complex. The complexity of albinism was hinted at, in early publications, but has only recently been fully appreciated with the advent of molecular techniques. Currently, 12 different genes have been identified, that when mutated, result in a different type of albinism. Oculocutaneous albinism type 1 (OCA1), resulting from mutations of the tyrosinase gene, is genetically and biochemically the best understood type of albinism. Though much of the research in albinism has involved OCA1, there are many unanswered questions about OCA1 and albinism, in general. The next 100 yr should still provide many surprises as did the first 100 yr.     

Oculocutaneous albinism type 4: six novel mutations in the membrane-associated transporter protein gene and their phenotypes

Oculocutaneous albinism type 4 (OCA4) is an autosomal recessive hypopigmentary disorder caused by mutations in the Membrane-Associated Transporter Protein gene (SLC45A2). The SLC45A2 protein is a 530-amino-acid polypeptide that contains 12 putative transmembrane domains, and appears to be a transporter that mediates melanin synthesis. Eighteen pathological mutations have been reported so far. In this study, six novel mutations, p.Y49C (c.146A > G), p.G89R (c.265G > A), p.C229Y (c.686G > A), p.T437A (c.1309A > G), p.T440A (c.1318A > G) and p.G473D (c.1418G > A) were found in eight Japanese patients with various clinical phenotypes. The phenotypes of OCA4 were as various as the other types of OCA and probably depended on the mutation sites in the SLC45A2 gene.     

Oculocutaneous albinism type 4: six novel mutations in the membrane‐associated transporter protein gene and their phenotypes

Oculocutaneous albinism type 4 (OCA4) is an autosomal recessive hypopigmentary disorder caused by mutations in the Membrane‐Associated Transporter Protein gene (SLC45A2). The SLC45A2 protein is a 530‐amino‐acid polypeptide that contains 12 putative transmembrane domains, and appears to be a transporter that mediates melanin synthesis. Eighteen pathological mutations have been reported so far. In this study, six novel mutations, p.Y49C (c.146A > G), p.G89R (c.265G > A), p.C229Y (c.686G > A), p.T437A (c.1309A > G), p.T440A (c.1318A > G) and p.G473D (c.1418G > A) were found in eight Japanese patients with various clinical phenotypes. The phenotypes of OCA4 were as various as the other types of OCA and probably depended on the mutation sites in the SLC45A2 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     

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.     

Oculocutaneous albinism type 1: link between mutations,tyrosinase conformational stability,and enzymatic activity

Oculocutaneous albinism type 1 (OCA1) is an autosomal recessive disorder caused by mutations in the tyrosinase gene. Two subtypes of OCA1 have been described: severe OCA1A with complete absence of tyrosinase activity and less severe OCA1B with residual tyrosinase activity. Here, we characterize the recombinant human tyrosinase intramelanosomal domain and mutant variants, which mimic genetic changes in both subtypes of OCA1 patients. Proteins were prepared using site‐directed mutagenesis, expressed in insect larvae, purified by chromatography, and characterized by enzymatic activities, tryptophan fluorescence, and Gibbs free energy changes. The OCA1A mutants showed very low protein expression and protein yield and are enzymatically inactive. Mutants mimicking OCA1B were biochemically similar to the wild type, but exhibited lower specific activities and protein stabilities. The results are consistent with clinical data, which indicates that OCA1A mutations inactivate tyrosinase and result in severe phenotype, while OCA1B mutations partially inactivate tyrosinase and result in OCA1B albinism.     

Oculocutaneous albinism in the i6 mutant of the medaka fish is associated with a deletion in the tyrosinase gene.

Three mutant alleles (i1, i4, and i5) of the tyrosinase gene in the i locus of the medaka fish Oryzias latipes have hitherto been described, all being associated with transposable element insertion. We have recently identified another allele causing a complete albino phenotype in homozygous carriers and named it i6. Sequence comparison between the tyrosinase gene for the i6 allele (Tyr-i6) and the wild-type gene previously obtained (Tyr-i+) revealed three deletions of 8, 44, and 245 bp. The first two deletions reside in an intron and are differences in the number of tandem tetranucleotide repeats that are polymorphic even among wild-type genes, and, thus, not likely to be responsible for the i6 albino phenotype. The largest deletion spans over the last 180 bp of the second intron and the first 65 bp of the third exon. Because of this deletion, the Tyr-i6 gene lacks the branch point sequence and the acceptor site for the second intron, both being considered to be necessary for normal RNA splicing. Therefore, the 245-bp deletion is likely to be responsible for the albino phenotype. With a mutant gene of this type, unlike ones bearing transposable element insertions, the possibility of reversion mutations to the wild-type would be negligible. Therefore, fish having the i6/i6 genotype should serve as superior recipients for the tyrosinase gene in rescue experiments.     

Identification and characterization of the compound heterozygous variants of TYR gene in a northern Chinese family with Oculocutaneous albinism type 1

Oculocutaneous albinism (OCA) is a genetically heterogeneous disease and is most inherited in an autosomal recessive manner. The characteristic manifestation of OCA is due to disfunction of melanin synthesis. OCA1 is the most severe subtype of OCA and is caused by homozygous or compound heterozygous variants in tyrosinase (TYR) gene, which is the key gene for melanin synthesis. This study aimed to identify the genetic variants of a northern Chinese family with OCA1. Clinical information and peripheral blood samples were collected. PCR amplification and Sanger sequencing were used to detect the entire exons and adjacent flanking sequences of TYR gene. Functional prediction of variants was performed by various bioinformatic analyses, while the pathogenicity classification of variants was evaluated according to ACMG standards and guidelines. A missense variant NM_000372.5:c.107G > C;NP_000363.1:p.C36S was discovered in TYR gene which converted cysteine to serine. Another variant in intron, NM_000372.5:c.1037–7 T > A, also affected the function of TYR gene. We verified the pathogenicity of the intron variant with a pCAS2 mini-gene based splicing assay and found that c.1037–7 T > A led to an insertion of 5 bp upstream from the common acceptor site of exon 3, which caused a frameshift TYR:c.1037–7 T > A:p.G346Efs*11. The results showed that the compound heterozygous variants c.107G > C:p.C36S and c.1037–7 T > A:p.G346Efs*11 of TYR gene were the pathogenic variants for this OCA1 family.     

The most common fragile site in man is 3p14

Summary In man a common fragile site is known to occur at 3p14. We studied the expression of this fragility in a group of 70 normal healthy subjects. Chromosome breaks, chromatid breaks and gaps at 3p14 could be observed in every examined individual, and in a total of 7000 metaphases they were seen in a mean of 4% of cells. Fluorescence studies in ten persons with chromosome No. 3 polymorphism showed that in all cases both Nos. 3 were about equally liable to breakage. A considerable variation in the fra 3p14 expression was found between individuals as well as in repeated cultures from the same person. Neither sex nor age influences could be detected. Cultures with a high percentage of lesions at 3p14 tended to have also a high number of lesions at other sites. Methotrexate and fluorodeoxyuridine markedly enhanced the expression of fra 3p14 and other fragilities. It is concluded that the chromosomal region at 3p14 represents man's most common fragile site, the expression of which seems to be influenced by environmental and heritable factors.     

Trypanosoma vivax: mechanical transmission in cattle by one of the most common African tabanids,Atylotus agrestis

The role of mechanical vectors in the transmission of African livestock trypanosomes has always been controversial relative to tsetse flies, their cyclical vectors. An experiment was carried out in Burkina Faso to demonstrate mechanical transmission of Trypanosoma vivax by one of the most common tabanids in Africa: Atylotus agrestis. Eight heifers (crossbred zebuxBaoulé), free of trypanosome infection, were kept in a corral covered by a mosquito net, together with two heifers infected experimentally with a local stock of T. vivax. On average, 324 A. agrestis, freshly captured with Nzi traps, were introduced daily over 20 days. Parasitological, PCR and serological examinations were carried out regularly to assess infections and levels of parasitaemia. Microscopic examination of buffy-coats indicated that five of the eight receiver-heifers were infected on days 8, 13, 32, 41, and 48. PCR results indicated that these five heifers were already infected by day 13. Mechanical transmission of T. vivax by A. agrestis was demonstrated unequivocally, at a high rate (63% in 13-20 days). Conditions of transmission in this experiment are discussed in terms of natural rates of challenge. The importance of tabanids as mechanical vectors of T. vivax should be re-considered, in light of these results. Creation of tsetse free zones in Africa will generally lead to the disappearance of T. congolense, T. brucei, and most often T. vivax as well; however, in areas where T. vivax can be mechanically transmitted, clearance of tsetse may not be sufficient to eradicate livestock trypanosomosis.     

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.     

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.     

New mutations identified in the ocular albinism type 1 gene

As the most common form of ocular albinism, ocular albinism type I (OA1) is an X-linked disorder that has an estimated prevalence of about 1:50,000. We searched for mutations through the human genome sequence draft by direct sequencing on eighteen patients with OA1, both within the coding region and in a thousand base pairs upstream of its start site. Here, we have identified eight new mutations located in the coding region of the gene. Two independent mutations, both located in the most carboxyterminal protein regions, were further characterized by immunofluorescence confocal microscopy, thus showing an impairment in their subcellular distribution into the lysosomal compartment of Cos-7A cells. The mutations found can result in protein misfolding, thus underlining the importance of the structure-function relationships of the protein as a major pathogenic mechanism in ocular albinism. Seven individuals out of eighteen (38.9%) with a clinical diagnosis of ocular albinism showed mutations, thus underlining the discrepancies between the clinical phenotype features and their genotype correlations. We postulate that mutations that have not yet been identified are potentially located in non-coding conserved regions or regulatory sequences of the OA1 gene.