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.     

Detection of heterozygotes for tyrosinase-negative oculocutaneous albinism by hairbulb tyrosinase assay.

Five heterozygotes for ty-neg OCA had absent or markedly reduced hairbulb tyrosinase activity, when compared to normally pigmented control subjects. Clinically, all five were fully pigmented and could not be distinguished from the normal control subjects. It is proposed that the quantitative hairbulb tyrosinase assay can be used to detect heterozygotes for ty-neg OCA. A mechanism to explain the low levels of activity in the hairbulbs from heterozygotes is discussed.     

眼皮肤白化病分型及珊基因新突变的鉴定

目的了解我国眼皮肤白化病（oculocutaneous albinism,OCA）的分型和相关基因突变类型,探讨新突变可能的分子致病机制。方法应用PCR方法扩增TYR基因,经DNA序列测定检出突变,采用错配引物PCR进行新突变的群体筛查,结合生物信息学方法探讨一种新突变的致病性和可能的分子致病机制。结果10名患者中有5人存在2个突变TYR等位基因,共计8种突变类型,其中c．71G〉A（C24Y）和c．841G〉T（E281X）是OCA1A致病性新突变;C24极可能参与二硫键形成,C24Y将导致酪氨酸酶肽链内此二硫键消失,进而引起蛋白空间构象变化和功能异常而致病。结论从基因水平初步了解了我国OCA1所占的比例,探讨了TYR基因C24Y的致病性并初步阐明了其致病的分子机制。本结果丰富了人类TYR基因突变类型,为我国OCA分型诊断、产前基因诊断和遗传咨询等积累了有价值的数据资料。     

Characterization of melanosomes and melanin in Japanese patients with Hermansky–Pudlak syndrome types 1, 4, 6, and 9

Hermansky–Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism (OCA), a bleeding tendency, and ceroid deposition. Most of the causative genes for HPS encode subunits of the biogenesis of lysosome‐related organelles complex (BLOC). In this study, we identified one patient each with HPS4, HPS6, and HPS9 by whole‐exome sequencing. Next, we analyzed hair samples from the three patients and representative patients with HPS1 and controls using electron microscopy and chemical methods. All HPS patients had fewer, smaller, and more immature melanosomes than healthy controls. Further, all patients showed reduced total melanin content and increased levels of benzothiazine‐type pheomelanin. The results of this study demonstrate the impact of the dysfunctions of BLOCs on the maturation of melanosomes and melanin levels and composition through analysis of their hair samples.     

Analysis of Mutations in the Copper B Binding Region Associated With Type I (Tyrosinase-Related) Oculocutaneous Albinism

Mutations of the tyrosinase gene are responsible for type I (tyrosinase-related) oculocutaneous albinism (OCA), an autosomal recessive genetic syndrome with a broad phenotypic spectrum. Mutant tyrosinase alleles can be associated with no melanin synthesis (I-A, tyrosinase-negative OCA), small to moderate amounts of melanin (I-B, yellow OCA) or unusual pigment patterns (I-TS, temperature-sensitive OCA). A total of 26 mutations of this gene have been described in type I OCA. Analysis of all known missense mutations (n = 17) shows that most cluster in three areas of the coding region. Two clusters involve the copper A or copper B binding sites and may disrupt the metal ion-protein interaction necessary for enzyme function and the third cluster is located in exon I. Computer modeling of the secondary structure of the copper binding regions based on homology with the known crystal structure of hemocyanin show that they both consist of two a helicies containing three histidine ligands that complex to a single copper atom. Mutations in the copper B binding region lie in the region between the two a helices that consists of a loop structure. These mutations may affect tyrosinase activity by either altering the position of the a helical domains and thus preventing proper copper binding to the histidine ligands, or affecting a catalytic or substrate binding site located between the two a helical domains.     

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.     

Two Novel Tyrosinase (TYR) Gene Mutations with Pathogenic Impact on Oculocutaneous Albinism Type 1 (OCA1)

Oculocutaneous albinism (OCA) is a heterogeneous group of autosomal recessive disorders resulting from mutations of the tyrosinase (TYR) gene and presents with either complete or partial absence of pigment in the skin, hair and eyes due to a defect in an enzyme involved in the production of melanin. In this study, mutations in the TYR gene of 30 unrelated Iranian OCA1 patients and 100 healthy individuals were examined using PCR-sequencing. Additionally, in order to predict the possible effects of new mutations on the structure and function of tyrosinase, these mutations were analyzed by SIFT, PolyPhen and I-Mutant 2 software. Here, two new pathogenic p.C89S and p.H180R mutations were detected in two OCA1 patients. Moreover, the R402Q and S192Y variants, which are common non-pathogenic polymorphisms, were detected in 17.5% and 35% of the patients, respectively. The outcome of this study has extended the genotypic spectrum of OCA1 patients, which paves the way for more efficient carrier detection and genetic counseling.     

Hermansky-Pudlak syndrome and related disorders of organelle formation

Hermansky-Pudlak syndrome (HPS) consists of a group of genetically heterogeneous disorders which share the clinical findings of oculocutaneous albinism, a platelet storage pool deficiency, and some degree of ceroid lipofuscinosis. Related diseases share some of these findings and may exhibit other symptoms and signs but the underlying defect in the entire group of disorders involves defective intracellular vesicle formation, transport or fusion. Two HPS-causing genes, HPS1 and ADTB3A, have been isolated but the function of only the latter has been determined. ADTB3A codes for the beta 3A subunit of adaptor complex-3, responsible for vesicle formation from the trans-Golgi network (TGN). The many HPS patients who do not have HPS1 or ADTB3A mutations have their disease because of mutations in other genes. Candidates for these HPS-causing genes include those responsible for mouse models of HPS or for the 'granule' group of eye color genes in Drosophila. Each gene responsible for a subset of HPS or a related disorder codes for a protein which almost certainly plays a pivotal role in vesicular trafficking, inextricably linking clinical and cell biological interests in this group of diseases.     

Hermansky–Pudlak Syndrome and Pale Ear: Melanosome‐Making for the Millennium

Hermansky–Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized principally by oculocutaneous albinism, a bleeding tendency, and a ceroid‐lipofuscin lysosomal storage disease. These clinical manifestations of HPS are associated with defects of multiple cytoplasmic organelles – melanosomes, platelet granules, and lysosomes – suggesting that the HPS gene product is involved in some shared feature of the biogenesis or functions of these diverse organelles. The HPS gene has been cloned, and a number of pathologic mutations of the gene have been identified. Functional studies indicate that the HPS protein is part of a high‐molecular weight complex involved in the biogenesis of early melanosomes. Additional disorders with similarities to HPS have been identified in man, mouse, flies, and yeast, and it is rapidly becoming clear that understanding these disorders will shed new light on the mechanisms by which cells traffic newly synthesized proteins through the cytoplasm to assemble functional organelles.     

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.     

The tyrosinase gene and oculocutaneous albinism type 1 (OCA1): A model for understanding the molecular biology of melanin formation

Through the last century there has been a steady progression in our understanding of the biology of melanin biosynthesis. Much of this work includes the analysis of coat color mutations of the mouse and albinism in man. Our understanding has been greatly enhanced in the last 10 years, as the molecular pathogenesis of albinism has been better understood. Different mutations of the tyrosinase gene (TYR) , and their association with oculocutaneous albinism type 1 (OCA1) has provided insight into the biology of tyrosinase, including protein trafficking and structure/function analysis. Several questions still remain, including cryptic mutations that affect tyrosinase activity and the minimum amount of pigment required for normal optic development. The next 10 years should prove just as exciting as the last.     

一种新型眼皮肤白化病——OCA4

眼皮肤白化病(OCA)在遗传学上是一组由不同基因的突变导致的具有相同或相似临床症状的遗传病。根据涉及基因的不同, OCA进一步分为4型, 即眼皮肤白化病Ⅰ~Ⅳ型(OCA1~OCA4)。OCA4为近年新发现的一种眼皮肤白化病类型, 首报病例是一名土尔其后裔。与小鼠uw基因同源的MATP基因突变导致OCA4表型的发生。MATP 基因定位于5p13.3, 由7个外显子和6个内含子构成, MATP基因在转录水平上受黑素细胞特异性转录因子调控, 编码由530个氨基酸残基构成的膜相关转运蛋白。迄今, 至少已报道了18种MATP基因病理性突变和8种DNA多态性变异。     

NGS‐based targeted resequencing identified rare subtypes of albinism: Providing accurate molecular diagnosis for Japanese patients with albinism

Albinism, which is commonly inherited as an autosomal recessive trait, is characterized by a reduction or absence of melanin in the eyes, skin, and hair. To date, more than 20 causal genes for albinism have been identified; thus, the accurate diagnosis of albinism requires next‐generation sequencing (NGS). In this study, we analyzed 46 patients who tested negative for oculocutaneous albinism (OCA)1–4 and Hermansky‐Pudlak syndrome (HPS)1 based on conventional analysis, in addition to 28 new Japanese patients, using NGS‐based targeted resequencing. We identified a genetic background for albinism in 18 of the 46 patients (39%), who were previously tested negative according to the conventional analysis. In addition, we unveiled a genetic predisposition toward albinism in 23 of the 28 new patients (82%). We identified six patients with rare subtypes of albinism, including HPS3, HPS4, and HPS6, and found 12 novel pathological mutations in albinism‐related genes. Furthermore, most patients who were not diagnosed with albinism by the NGS analysis showed mild manifestations of albinism without apparent eye symptoms and harbored only one heterozygous mutation, occasionally in combination with skin‐color associated gene variants.     

A clinical variant of familial Hermansky-Pudlak syndrome

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive inherited disease consisting of (1) partial oculocutaneous albinism (with nystagmus, strabism, and visual acuity loss), (2) platelet storage pool deficiency (with bleeding diathesis), and (3) disorder of "ceroid" metabolism with a multisystem tissue lysosomal ceroid deposition. HPS is less uncommon in Puerto Rico, where the most important studies have been performed, but is a very rare disease in Europe. HPS basic defect remains unknown, even if an HPS-causing gene was identified in chromosome segment 10q23-q23.3, and several mutations have been reported. The aim of this article is to discuss, on the basis of a review of relevant literature, a new familial HPS clinical variant observed in 2 young sisters (aged 16 and 23 years old, respectively), characterized by the typical symptoms of this syndrome. Our patients also suffered from diffuse interstitial pulmonary disease and an unexpectedly increased platelet aggregation and were prone to bacterial infections. Interestingly, we observed urinary tract abnormality in the younger HPS sister and a porencephalic cyst in the older HPS sister; both of these developmental defects have been reported in the Cross syndrome (or oculocerebral hypopigmentation syndrome). It seems that in our patients, an overlapping of the phenotypic manifestations of different rare syndromes may be present. The presence of ceroid-like autofluorescent material in urinary sediment together with the histologic aspects and the autofluorescence of oral mucosa biopsy are consistent with a ceroid-like lipofuscin storage. HPS should be carefully tested for in suspected cases to prevent the severe visual impairment, rapidly progressive pulmonary fibrosis, and other complications associated with this disorder.     

Analysis of Tyrosinase Mutations Associated With Tyrosinase-Related Oculocutaneous Albinism (OCAI)

Mutations of the tyrosinase gene associated with a partial or complete loss of enzymatic activity are responsible for tyrosinase related oculocutaneous albinism (OCA1). A large number of mutations have been identified and their analysis has provided in-sight into the biology of tyrosinase and the pathogenesis of these different mutations. Missense mutations produce their effect on the activity of an enzyme by altering an amino acid at a specific site. The location of these mutations in the peptide can be used to indicate potential domains important for enzymatic activity. Missense mutations of the tyrosinase polypeptide cluster in four regions, suggesting that these are important functional domains. Two of the potential domains involve the copper binding sites while the others are likely involved in substrate binding. More critical analysis of the copper binding domain of tyrosinase can be gained by analyzing the structure of hemocyanin, a copper-binding protein with a high degree of homology to tyrosinase in the copper binding region. This analysis indicates a single catalytic site in tyrosinase for all enzymatic activities.     

The Tyrosinase Gene in Gorillas and the Albinism of ‘Snowflake’

The sequence of the tyrosinase (Tyr) gene coding tracts has been obtained for the gorilla (Gorilla gorilla gorilla). The five exons of the gene were sequenced in three gorillas and in a normally pigmented human. The tyrosinase gene has been found to be a very conserved locus with a very low substitution rate. Some nucleotide and amino acid differences were found between the gorilla and human tyrosinase coding sequences. One of the gorillas included in the study is the only known case of albinism in a gorilla (‘Snowflake’). Mutations of the TYR gene lead to Oculocutaneous Albinism type 1 (OCA1), the most common type of albinism in humans (OMIM accession number 203100). The TYR gene encodes the tyrosinase enzyme (E.C. 1.14.18.1), whose activity was found to be completely lacking in ‘Snowflake’, indicating that a mutation in the Tyr gene is the likely cause of his albinism. Nonetheless, no nucleotide changes were detected that could account for the lack of Tyr product or tyrosinase activity in Snowflake, and explanations of these findings are discussed.     

Prenatal Genotyping of Four Common Oculocutaneous Albinism Genes in 51 Chinese Families

Oculocutaneous albinism(OCA)is an autosomal recessive disorder characterized by hypopigmentation in eyes,hair and skin,accompanied with vision loss.Currently,six genes have been identified as causative genes for non-syndromic OCA(OCA-1w4,6,7),and ten genes for syndromic OCA(HPS-1e9,CHS-1).Genetic counseling of 51 Chinese OCA families(39 OCA-1 with mutations in the TYR gene,6 OCA-2 with mutations in the OCA2 gene,4 OCA-4 with mutations in the SLC45A2 gene,1 HPS-1(Hermanskye Pudlak syndrome-1)with mutation in the HPS1 gene,and 1 mixed OCA-1 and OCA-4)led us to perform the prenatal genetic testing of OCA using amniotic fluid cells through the implementation of our optimized strategy.In our cohort,eleven previously unidentified alleles(PUAs)(5 in TYR,2 in OCA2,and 4 in SLC45A2)were found.Three missense PUAs(p.C112R,p.H363R and p.G379V of TYR)and one in-frame deletional PUA(p.S222del of SLC24A5)led to fetuses with OCA when co-inherited with other disease causative alleles.Three PUAs(p.P152H and p.W272X of TYR,p.A486T of SLC24A5)identified in the OCA probands did not co-transmit with known pathological alleles and thus gave rise to unaffected fetuses.Four PUAs(p.Q83X and p.A658T of TYR,p.G161R and p.G366R of SLC24A5)did not transmit to the unaffected fetuses.In addition,the in vitro transfection assays showed that the p.S192Y variant of TYR produced less pigment compared to the wild-type allele.A fetus with a digenic carrier of OCA-1 and OCA-4 was unaffected.In combination with functional assays,the family inheritance pattern is useful for the evaluation of pathogenicity of PUAs and genetic counseling of OCA.     

Instability of BLOC‐2 and BLOC‐3 in Chinese patients with Hermansky‐Pudlak syndrome

Hermansky‐Pudlak syndrome (HPS) is a rare recessive disorder characterized by oculocutaneous albinism (OCA) or ocular albinism (OA), bleeding tendency, and other symptoms due to multiple defects in tissue‐specific lysosome‐related organelles. Ten HPS subtypes have been characterized with mutations in HPS1 to HPS10, which encode the subunits of BLOC‐1, ‐2, ‐3, and AP‐3. Using next‐generation sequencing (NGS), we have screened 100 hypopigmentation genes in OCA or OA patients and identified four HPS‐1, one HPS‐3, one HPS‐4, one HPS‐5, and three HPS‐6. The HPS‐4 case is the first report in the Chinese population. Among these 20 mutational alleles, 16 were previously unreported alleles (6 in HPS1, 1 in HPS3, 2 in HPS4, 2 in HPS5, and 5 in HPS6). BLOC‐2 and BLOC‐3 were destabilized due to the mutation of these HPS genes which are so far the only reported causative genes in Chinese HPS patients, in which HPS‐1 and HPS‐6 are the most common subtypes. The mutational spectrum of Chinese HPS is population specific.