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PubMed1992

Cloning and sequence analysis of the tyrosinase gene from a patient with tyrosinase-positive oculocutaneous albinism.

Tyrosinase is synthesized on membrane-bound ribosomes and transported into melanosomes through smooth endoplasmic reticulum and Golgi apparatus. Melanin polymers are produced only in melanosomes but never in smooth endoplasmic reticulum or Golgi apparatus, indicating that posttranslational modifications of tyrosinase are completed with melanosomes where tyrosinase becomes an active form. Based on a working hypothesis that tyrosinase-positive oculocutaneous albinism is a consequence of the structurally altered tyrosinase due to a point mutation in the gene of its gene coding for a glycosylation site or a membrane-binding site, which leads to the impairment in the posttranslational modification of tyrosinase and its catalytic activity, we have cloned the tyrosinase gene of one patient affected with tyrosinase-positive oculocutaneous albinism and determined its nucleotide sequence. Thus demonstrated all exons' nucleotide sequence of the patient's tyrosinase gene was found to be identical to that of the wild-type gene. The results indicate that the patient's tyrosinase itself is not altered. We therefore propose that the molecular basis for the development of tyrosinase-positive oculocutaneous albinism exists as a defect in other proteins required for the activation of tyrosinase or in other regions of the tyrosinase gene.

Adult↗
PubMed2005

Papillon-Lefèvre syndrome with albinism: a review of the literature and report of 2 brothers.

BACKGROUND: Papillon-Lefèvre syndrome (PLS) is a very rare autosomal recessive disorder characterized by palmoplantar hyperkeratosis and severe early onset of destructive periodontitis leading to premature loss of both primary and permanent dentitions. The etiopathogenesis of the condition suggests that there is a genetic basis for susceptibility to specific virulent pathogens. Variation in the clinical presentation of PLS has recently been observed. OBJECTIVE: The objective was to present the first report, which describes the concurrence of PLS and albinism. The etiology, pathology, and management of the condition were reviewed and genetic analysis was performed. SUBJECTS AND CLINICAL PRESENTATION: The probands are Jordanian brothers aged 13 and 20 years on their initial presentation. The parents were second cousins and not affected. The patients exhibited the typical clinical features of PLS with type 1 oculocutaneous albinism (OCA1). They also had increased susceptibility to infection manifested in recurrent tonsillitis, respiratory tract infection, pyoderma, onychogryphosis, and other pathosis. Skin biopsy demonstrated hyperkeratosis, focal parakeratosis, hypergranulosis, and acanthosis. Ectopic calcification of the dura was noticed in one of the probands. Hematological parameters tested were within the normal limits. The probands were tested for mutations in the causative genes of PLS and OCA1, cathepsin C (CTSC), and tyrosinase, respectively. Independent mutations (c.318-1G>A and c.817G>C/p.W272C) were identified in CTSC and tyrosinase, respectively. The probands were homozygous and their sister who had only PLS was homozygous for the same (CTSC) mutation but heterozygous for tyrosinase gene. CONCLUSION: We hope that this report of coinheritance PLS and albinism will initiate further investigations to disclose other possible variations that may enhance our knowledge on gene mutations of this intriguing syndrome.

Adolescent↗
PubMed1996

Diagnosis of oculocutaneous albinism with molecular analysis.

PURPOSE: To use molecular analysis to diagnose oculocutaneous albinism in a patient with an atypical clinical presentation. METHODS: A 34-year-old woman with a history of strabismus and absent cutaneous pigment underwent comprehensive ophthalmic examination, visual-evoked potentials to detect altered optic decussation, and molecular analysis. RESULTS: Examination showed fine nystagmus, iris transillumination, foveal hypoplasia, and corrected visual acuity of 20/25 in each eye. Misrouting of the retinostriate fibers was demonstrated with visual-evoked potentials. Mutations in the tyrosinase gene established the diagnosis of oculocutaneous albinism 1 even though the patient had atypical clinical features. CONCLUSIONS: Molecular analysis can establish the diagnosis of oculocutaneous albinism 1 in the patient with atypical ocular features.

Adult↗
PubMed1985

Brown oculocutaneous albinism. Clinical, ophthalmological, and biochemical characterization.

The clinical, ophthalmological, and biochemical characteristics of a 28-year-old black woman with brown oculocutaneous albinism were determined. Hair color was medium brown and skin color was light brown, and a faint tan developed with sun exposure. The irides were light brown in the central one-third, blue-gray in the peripheral two-thirds, and showed punctate and radial translucency. Visual acuity was 20/60 in the right eye and 20/100 in the left eye. There was a moderate pendular nystagmus, and previous surgeries had corrected an exotropia. The foveal reflex was muted, and the retinal pigment was reduced. Hairbulb tyrosinase activity was 1.75 pmoles/120 min/hairbulb, hairbulb glutathione content 0.83 nmoles/hairbulb, and urine excretion of 5-S-cysteinyldopa 174.9 ng/mg creatinine. Electron microscopy of hairbulb and skin melanocytes showed arrested melanosomal development. These findings suggest that there is a partial block in the distal eumelanin pathway in this form of albinism. The ophthalmological characteristics of six additional cases of this form of albinism are also presented.

Adult↗
PubMed2003

A novel P gene missense mutation in a Japanese patient with oculocutaneous albinism type II (OCA2).

BACKGROUND: Oculocutaneous albinism type II (OCA2) is an autosomal recessively inherited disorder, characterized by white hair and skin, and loss of pigment in the eyes. Mutations in P gene have been shown to result in OCA2. So far, two cases have been reported from Japan. OBJECTIVE: We had an opportunity to examine a case of albinism, and screened the mutations of tyrosinase and P gene. METHODS: Genomic DNA was prepared from peripheral leukocytes. All of the exons and flanking introns of tyrosinase and P gene were PCR-direct-sequenced. RESULTS: Although no mutations were found in tyrosinase, we found two missense substitutions, A481T and Q799H in P gene. The A481T has previously been shown to result in partial function of the P protein. CONCLUSION: The Q799H mutation is not a common polymorphism among normal Japanese, seems most likely to be a pathological OCA2 mutation among Japanese with this form of albinism.

Albinism, Oculocutaneous↗
PubMed1999

Bilateral abortive cryptophthalmos associated with oculocutaneous albinism.

PURPOSE: To document a case of bilateral abortive cryptophthalmos associated with oculocutaneous albinism. METHODS: We describe a 13-year-old female patient with blond skin and hair who had anomalous face and eyes first noted at birth. RESULTS: The patient had fair hair and complexion, bilateral anomalous wedge of scalp hair, upper eyebrow and eyelid deformities, cup-shaped ears, broad based nose with depressed bridge and midline groove, iris transillumination and diffuse hypopigmentation and foveal hypoplasia in fundus examination. CONCLUSION: Based on the clinical and laboratory findings, the reported case represents tyrosinase-positive oculocutaneous albinism together with bilateral abortive cryptophthalmos. The oculocutaneous albinism can either be an entirely new criterion to the whole syndrome of cryptophthalmos, or, more probably, the condition can be due to a double affliction which is primarily related with consanguinity of the parents. The importance of ante-natal diagnosis and genetic counseling are emphasized in such cases where the two recessive genes for two different conditions coexist.

Adolescent↗
PubMed2000

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.

Albinism, Oculocutaneous↗
PubMed2001

Intracellular distribution and late endosomal effects of the ocular albinism type 1 gene product: consequences of disease-causing mutations and implications for melanosome biogenesis.

To investigate the function of ocular albinism type 1 (OA1), the gene responsible for X-linked ocular albinism, we employed a construct containing murine Oa1 fused to green fluorescent protein (GFP) in a heterologous COS cell expression system. The cellular distribution of wild-type (WT) Oa1 protein and Oa1 proteins reflecting mutations causing X-linked ocular albinism were examined. Comparison with different organelle markers revealed that Oa1-GFP localized to the late endolysosomal compartments. Some Oa1 mutant proteins failed to exit the endoplasmic reticulum (ER) (Class I mutants), while other mutants partially (Class II mutants) or fully (Class III mutants) exited the ER and trafficked to endolysosomal compartments. We observed that expression of WT Oa1-GFP in COS cells caused an apparent enlargement of late endosomes and a redistribution of the mannose-6-phosphate receptor (M6PR). None of the mutants displayed the full range of effects on the redistribution of M6PR exhibited by WT Oa1. The effects of Oa1 on late endosome structure and content are thus likely to reflect an important biological property of Oa1. We propose that OA1 is involved in reorganizing the endolysosomal compartment as a necessary step in ocular melanosome biogenesis.

Albinism, Ocular↗
PubMed2000

Non-bullous congenital ichthyosiform erythroderma, with ocular albinism and Noonan syndrome.

A 21-year-old woman presented with non-bullous congenital ichthyosiform erythroderma; she was born a collodion baby. Associated features were ocular albinism, anterior segment dysgenesis of both eyes and Noonan syndrome. X-linked ichthyosis (steroid sulphatase deficiency) and X-linked ocular albinism have been mapped to the Xp22.3 region and cases have been reported with both conditions due to a partial short-arm deletion of the X chromosome. The ichthyosis and ocular albinism in the present case, however, are likely to be of the autosomal recessive type - a very rare association - and the combination with Noonan syndrome has not been reported previously.

Adult↗
PubMed2003

Oculocutaneous albinism.

Oculocutaneous albinism represents a group of inherited skin disorders characterized by a generalized reduction of cutaneous, ocular and pilar pigmentation from the time of birth. Oculocutaneous albinism types 1 and 2 are the most common, but several other types have been described. A defect in the melanin synthesis pathway, resulting in reduced formation of melanin, is responsible for oculocutaneous albinism. Aetiology, clinical manifestations, diagnosis and management are discussed.

Albinism, Oculocutaneous↗
PubMed2003

[Anatomical differences in optic nerve, chiasma and tractus opticus in human albinism as demonstrated by standardised clinical and MRI evaluation].

BACKGROUND: There has been long-standing clinical and electrophysiological evidence that in patients with albinism the visual pathways cross atypically: most fibres from one eye cross to the contralateral visual cortex. PURPOSE OF THE STUDY: to determine whether the size and configuration of the optic chiasm in human albinos is different from normally pigmented controls. PATIENTS AND METHODS: 17 patients (11 female, mean age 35.8 years) with oculocutaneous albinism underwent a standardised graded morphological and functional evaluation. Magnetic resonance images were reformatted to the region of the optic chiasm and analysed using observer-independent morphometry. In addition, fMRI of the visual cortex was performed during VEP analysis (1.5 Tesla Siemens Vision). Morphological and fMRT results were compared to an age-correlated group of n = 16 normally pigmented healthy volunteers with normal visual acuity and stereopsis. RESULTS: 65 % of the patients (n = 10) showed signs of dysplasia of the optic nerve head. Statistical morphometry showed distinct differences in chiasmal morphology between albinos and normally pigmented probands (smaller optic nerves, different angles of optical entry into the chiasm and of the beginning of the Tractus optici leaving the chiasm, overall chiasmal width and height). CONCLUSIONS: Optic nerve head anomalies are frequent in albinism and influence visual outcome. Size and configuration of the optic chiasm in human albinos is distinctly different from normally pigmented control persons and reflects the atypical crossing of optic fibres.

Adult↗
PubMed1990

A frequent tyrosinase gene mutation in classic, tyrosinase-negative (type IA) oculocutaneous albinism.

We have identified a tyrosinase gene mutation in several patients with classic, tyrosinase-negative (type IA) oculocutaneous albinism. This mutation, which results in a proline----leucine substitution at codon 81 of the tyrosinase polypeptide (EC 1.14.18.1), was observed in 20% (6 of 30) of oculocutaneous albinism alleles from independent probands, but it was not observed in any normal individuals. This mutation thus appears to be a frequent cause of tyrosinase-negative oculocutaneous albinism.

Albinism↗
PubMed2003

Mutational analysis of the OA1 gene in ocular albinism.

Ocular albinism type 1 (OA1) is an X-linked disorder, mainly characterized by a severe reduction in visual acuity, foveal hypoplasia, nystagmus, hypopigmentation of the retina, the presence of macromelanosomes in the skin and eyes, and the misrouting of optic pathways, resulting in the loss of stereoscopic vision. We screened the OA1 gene for mutations in three unrelated Canadian and French families and in two isolated patients with OA1. We found three different missense mutations and two different nonsense mutations, three of which were novel. To date, 41 mutations (including missense mutations, insertions, and deletions) have been reported in the OA1 gene. Mutation and polymorphism data for this gene are available from the international albinism center albinism database website: http://www.cbc.umn.edu/tad/oa1map.htm.

Albinism, Ocular↗
PubMedDate not supplied

Oculocutaneous albinism in southern Africa: population structure, health and genetic care.

BACKGROUND: People with oculocutaneous albinism (OCA) have reduced levels of melanin in their hair, skin and eyes, with associated visual impairment and extreme sun sensitivity requiring lifelong monitoring. This genetic condition is surrounded by myth, superstition and fear in Africa, where affected individuals and their families may be rejected, shunned and excluded from their community. OBJECTIVE: This review reports population studies in southern Africa to determine the distribution of people with OCA in this predominantly rural and relatively impoverished area-crucial information for health and education providers. Health and genetic care studies document the range of eye and skin problems experienced and suggest effective and sustainable ways to manage these needs in a low resource setting. CONCLUSION: Innovative genetic care programmes in northern South Africa facilitate low-cost management of albinism, raise self-esteem and promote community awareness, helping to improve the long-term health prospects and social integration of those affected. This holistic approach of dealing with albinism from both a medical and a sociological perspective could be applied in other areas of Africa where this condition is prevalent.

Africa, Southern↗
PubMed2002

Diagnostic DNA testing for X-linked ocular albinism (OA1) with a hierarchical mutation screening protocol.

Albinism is a group of inherited conditions in which affected individuals have less than normal pigment in the eyes, skin, and hair compared to others of the same race and ethnic background. The prevalence of all types of albinism in the United States is estimated at 1 in 20,000, based on poor epidemiological data. X-linked Nettleship-Falls ocular albinism (XLOA, OA1) affects approximately 1/150,000 males in the population. XLOA effects reduce visual acuity and nystagmus, result in a mild skin and hair phenotype, and occur mostly in XY males. Female carriers of XLOA have normal visual acuity, but often show iris punctate transillumination and a classic pattern of mosaic retinal pigmentation, coarse and grainy in the macula and becoming increasingly reticular into the periphery of the retinal pigment epithelium. Studies of OA1 have shown linkage of a single gene to markers at Xp22.3-p22.2. About 48% of the reported mutations in the OA1 gene are intragenic deletions and about 43% are point mutations. We present a hierarchical strategy for mutation screening for diagnostic testing for OA1 that comprises two tiers: first, multiplex PCR to detect intragenic deletions in the OA1 gene with denaturing high-performance liquid chromatography (dHPLC), and, second, heteroduplex analysis with dHPLC to scan for mutations, with subsequent sequencing of variants to confirm putative mutations in the OA1 gene. Prenatal diagnosis can be provided for families when the mutation has been firmly identified. We have validated this procedure with positive controls that were identified in patients by Southern blot, single-stranded conformation polymorphism (SSCP), and sequencing. In this hierarchical strategy, these procedures have an analytical sensitivity of > 99%.

Albinism, Ocular↗
PubMedDate not supplied

Albinism in Icelandic sheep.

A description is given of complete albinism in Icelandic sheep. The albino animals, which have occurred both among white and nonwhite strains of sheep, are pure white in color with pink eyes and impaired vision in bright light. The condition is shown to be autosomal, recessive, and is assumed to be caused by a mutation of C to c, thereby being homologous to albinism in rodents. Data on mating results are tabulated. This is believed to be the first case of albinism reported in sheep.

Albinism↗
PubMedDate not supplied

Albinism in a Suffolk sheep.

This report introduces the second form of true albinism to be documented in sheep, which appears mild enough not to cause serious undesirable side effects yet apparently effective enough to have the potential for general usage in the sheep industry. Based on the matings conducted to date, the albinism is inherited like an autosomal recessive. Histochemical tests reveal a defective melanin synthesis involving a block to the conversion of tyrosine to dopa but not the subsequent reactions that lead to melanin. The enzyme tyrosinase is a product of the C locus and catalyzes the conversion of tyrosine to dopa and the following reaction (dopa to dopaquinone). Therefore, it is proposed that the albinism arises from a gene in the C locus that encodes a defective tyrosinase. The gene is provisionally named albino marrabel, the gene symbol is cmar, and the locus allele symbol is Ccmar.

Albinism↗
PubMed1996

Cloning of the murine homolog of the ocular albinism type 1 (OA1) gene: sequence, genomic structure, and expression analysis in pigment cells.

We report the isolation of the mouse homolog of OA1, the gene responsible for ocular albinism type 1. The mouse Oa1 gene encodes a putative protein of 405 amino acids displaying a high level of homology (78% identity, 87% similarity) to the human gene. All disease-associated missense mutations reported in patients with ocular albinism involve conserved amino acid residues in the mouse protein. Moreover, the murine homolog shows six putative transmembrane domains, as observed for the human gene, indicating that the overall structure of the two proteins is conserved. The genomic organization is also conserved between the two species across the entire coding region with splice sites located in the same positions. Like its human counterpart, the expression pattern of Oa1, apart from the eye, is restricted to the epidermal melanocyte lineage. A transcript of approximately 1.8 kb was readily detected by this probe in 5 out of 5 murine melanocyte lines, 4 out of 4 murine melanoblast lines, 1 out of 2 murine melanoma lines, and 1 out of 2 human melanoma lines tested, but it was not detected in 2 out of 2 lines of a developmentally earlier normal cell type, melanoblast precursor cells, suggesting that the gene is transcriptionally activated in epidermal melanocytes at the same stage as most other tested melanosomal proteins. Together, these data suggest that the function of the OA1 gene is conserved between human and mouse and point to the mouse as a model to facilitate the understanding of ocular albinism pathogenesis.

Albinism, Ocular↗