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PubMed1989

Electroretinographic findings in human oculocutaneous albinism.

Electroretinograms (ERGs) were obtained under dark- and light-adapted conditions from 15 human oculocutaneous albinos and compared with the results from a group of 30 normally pigmented subjects. Amplitude and implicit time measures of the ERG recordings obtained from six autosomal recessive and three autosomal dominant tyrosinase-positive albinos fell within the normal range. The six tyrosinase-negative albinos examined also had normal ERGs at low-to-moderate flash luminances. However, at the highest flash luminances, the dark-adapted ERGs of five such subjects were at or just above the normal range in amplitude, and were shorter than normal in implicit time. The dark-adapted luminance-response functions of these subjects were positioned normally on the luminance axis; light-adapted functions were shifted slightly to the left of normal. The possibility that anterior parts of the retina responding to light passing through the anterior eyewall may contribute to the ERGs obtained from tyrosinase-negative albinos was examined by recording dark-adapted ERGs with the sclera occluded. Amplitudes were reduced compared with those obtained with the sclera unoccluded, suggesting that responses to transscleral illumination contributed to the ERG in this type of albinism.

Adolescent↗
PubMed2000

Correlation of visual acuity and ocular pigmentation with the 16-bp duplication in the HPS-1 gene of Hermansky-Pudlak syndrome, a form of albinism.

OBJECTIVE: Patients with the Hermansky-Pudlak syndrome (HPS), a form of albinism, were studied. The first purpose of this investigation was to determine if visual acuity was related to the presence or absence of the 16-bp duplication in the HPS-1 gene. The second was to study the correlation between the degree of ocular pigmentation and visual acuity within the two genetic groups described above. DESIGN: Cross-sectional study of a series of consecutive patients. PARTICIPANTS: Forty-nine patients with HPS with or without the 16-bp duplication in HPS-1. METHODS: Best corrected visual acuity (VA) using Early Treatment Diabetic Retinopathy Study (ETDRS) charts, photographic gradings of iris transillumination and of visibility of choroidal vessels in the macula (macular transparency). MAIN OUTCOME MEASURES: Association between VA and the presence or absence of the 16-bp duplication in HPS-1 and correlation between VA and the degree of iris transillumination (iris score) and macular transparency (fundus score), as determined by masked reading of photographs, with respect to the presence or absence of the 16-bp duplication in HPS-1 were the main outcome measures. RESULTS: The VA of the better eye did not differ between the two genetic groups (P = 0.322, two-sided t test). Spearman's rank correlation between VA and iris scores in 39 eyes of 20 patients with the duplication was not statistically significant (P = 0.698) but was statistically significant in 36 eyes of 19 patients without the duplication (P < 0.001). Among all patients, the correlation was statistically significant (r = -0.36 in RE and r = -0.51 in LE). Spearman's rank correlation between VA and fundus scores in 36 eyes of 19 patients with and 34 eyes in 18 patients with and without the duplication was statistically significant (P = 0.035 and P = 0.008, respectively). Among all patients, it was also statistically significant (r = -0.39 in RE and r = -0.45 in LE). CONCLUSIONS: The mean VA of the better eye did not differ in patients with the 16-bp duplication compared with those without the duplication. There were statistically significant associations between VA and the iris score and the fundus score except for the VA and iris scores in patients with the 16-bp duplication. However, because of the variability of VA, these associations were not large enough for useful prediction of VA based on the degree of ocular pigmentation.

Adolescent↗
PubMed1998

Partial albinism with immunodeficiency: Griscelli syndrome: report of a case and review of the literature.

Partial albinism with immunodeficiency (Griscelli syndrome) is an uncommon disorder characterized by pigmentary dilution and variable immunodeficiency. Features include a silvery-gray sheen to the hair, large clumped melanosomes in hair shafts, and prominent mature melanosomes in cutaneous melanocytes with sparse pigmentation of adjacent keratinocytes. Immunologic abnormalities most often include impaired natural killer cell activity, absent delayed-type hypersensitivity, and impaired responses to mitogens. Impaired helper T cell function and hypogammaglobulinemia have also been described. The syndrome can be differentiated from Chediak-Higashi syndrome by pathognomonic light and electron microscopic features in skin and hair, and absence of consistent granulocyte abnormalities, but similarly carries a poor prognosis without bone marrow transplantation. We describe a patient with Griscelli syndrome who presented with hepatosplenomegaly, hepatitis, pancytopenia, and silvery hair in the newborn period.

Albinism↗
PubMed1992

Posterior chamber intraocular lens implantation in a patient with oculocutaneous albinism.

A 56-year-old woman with tyrosinase-negative oculocutaneous albinism complained of gradually decreasing vision in the left eye. Her visual acuity was 20/300 in the right eye and hand motion in the left eye. She had pink skin and white hair and cilia. On examination, bilateral hypopigmented irides, an opaque lens in the left eye, a hypopigmented fundus in the right eye, and nystagmus were found. An extra-capsular cataract extraction with posterior chamber intraocular lens (IOL) implantation was performed. After retrobulbar anesthesia was administered, the nystagmus ceased temporarily. Postoperatively, visual acuity in the left eye improved to 20/200. We believe IOL implantation is useful in the treatment of cataracts in albino patients.

Albinism, Oculocutaneous↗
PubMed2001

Albinism.

Albinism is a heterogeneous group of conditions having in common a hereditary error of melanin metabolism resulting in misrouting of optic nerve fibers during embryogenesis, underdevelopment of the neuroretinas, and in varying degrees of hypopigmentation of eyes, skin, and hair.

Albinism, Oculocutaneous↗
PubMed2002

A novel mutation of the tyrosinase gene causing oculocutaneous albinism type 1 (OCA1).

Tyrosinase is a rate-limiting enzyme in the melanin biosynthetic pathway and a complete defect of the enzyme activity caused by homozygous mutations of the tyrosinase gene is well known to result in tyrosinase-negative oculocutaneous albinism (OCA1A) patients who never develop any melanin pigment in the skin, hair and eyes throughout life. In this paper, we report a novel missense substitution, R239W(CGG --> TGG) of the tyrosinase gene in a patient with tyrosinase-negative OCA.

Albinism, Oculocutaneous↗
PubMed1996

R278TER and P431L mutations of the tyrosinase gene exist in Japanese patients with tyrosinase-negative oculocutaneous albinism.

We examined the tyrosinase gene of two Japanese patients with tyrosinase-negative oculocutaneous albinism by allele-specific amplification analysis on two known point mutations in Japanese, and the results indicated that they were compound heterozygouts, namely, one allele of the tyrosinase gene harbored one of two known mutations and another allele probably had a mutation unknown in Japanese patients. Therefore, we have cloned and sequenced the tyrosinase gene of the two patients and identified two different point mutations. One is a nonsense mutation, codon 278CGA (Arg) to TGA (TER), and the other is a substitution mutation, codon 431CCA (Pro) to CTA (Leu). However, these same mutations have already been observed in a Guyanan and a Moroccan Jewish patient, and in an Indo-Pakistani patient, respectively.

Albinism, Oculocutaneous↗
PubMed2002

The oculocutaneous albinism type IV gene Matp is a new marker of pigment cell precursors during mouse embryonic development.

Expression profile analysis demonstrated that the expression of membrane-associated transporter protein (MATP) varied similarly to the melanogenic enzymes dopachrome tautomerase (DCT) and tyrosinase related protein 1 (TYRP1) (Proc. Natl Acad. Sci. USA (2002) in press). Mutations in MATP result in pigmentation alterations in mice (underwhite, uw), in medaka (b-locus), and in man (Oculocutaneous Albinism Type 4, OCA4) (Nat. Genet. 28 (2001) 381; Am. J. Hum. Genet. 69 (2001) 981). Consistent with MATP acting in a pigment cell autonomous manner, in situ hybridization analysis demonstrated expression of murine Matp in the presumptive retinal pigmented epithelium starting at E9.5, and in neural crest-derived melanoblasts starting at E10.5. Matp expression is reduced in embryos mutated for microphthalmia-associated transcription factor (Mitf) (Cell 74 (1993) 395; J. Biol. Chem. 268 (1993) 20687), suggesting Mitf regulates Matp expression.

Albinism, Oculocutaneous↗
PubMed1998

Metastatic melanoma of the nasal cavity in a patient with oculocutaneous albinism.

The nasal cavity is a rare location for primary malignant melanoma, borne out by the few cases reported in the literature since 1940. Rarest of all is nasal melanoma in a patient with oculocutaneous albinism. An albino subject, aged 33, was referred to us with this diagnosis. Because of the numerous metastases in the liver and left lung, we did not advise radical surgical intervention and, despite hyperfractionated high dose radiotherapy and chemo-immunotherapy, the advanced stage of disease caused the death of the patient within a year. We have reviewed the diagnostic, clinical and therapeutic aspects, and the literature on melanomas of the nasal cavity in albino subjects. We performed a Medline literature search, examining only 'extensive' papers and excluding abstracts or case reports presenting poor data.

Adult↗
PubMed1999

Visual evoked potential evidence of albino-like chiasmal misrouting in a patient with Angelman syndrome with no ocular features of albinism.

An 8-month-old boy with global developmental delay, including visual and hearing inattention, was examined in the ophthalmic clinic. Monocular flash visual evoked potentials demonstrated a crossed asymmetry in scalp distribution, a feature considered to be pathognomic of albinism. Remarkably a foveal reflex was noted in each eye and this patient did not have nystagmus, iris transillumination, nor conspicuously pale fundi. The optic discs appeared normal. He was noted to have very fair skin and hair, with a small head and flat occiput. Cytogenetic studies demonstrated a microdeletion of the maternal chromosome 15q11-q13, and he was diagnosed with Angelman syndrome.

Albinism↗
PubMed1998

Toward expression mapping of albinism-deafness syndrome (ADFN) locus on chromosome Xq26.

We have employed a direct cDNA selection methodology to isolate transcribed sequences encoded in the human chromosomal interval Xq26 that contains the gene for X-chromosome linked albinism deafness syndrome (ADFN). ADFN had been previously mapped to an 8 centi Morgan region on chromosome Xq26. We have constructed six cDNA libraries specific to six YACs mapping to a 1.5 mb span at the distal boundary of the ADFN locus. The YAC specific libraries were characterized for the presence of unique cDNAs. We have identified 15 transcribed sequences from the selected cDNA libraries. These cDNAs matched to three well characterized sequences corresponding to steroid 5-alpha reductase, ribosomal protein L28, and a short transcript that has been shown to be expressed in human brain cortex. Seven of the cDNAs matched to expressed sequence tags or other sequences of unknown function, and five cDNAs shared no homology with sequences in the public data bases. Each one of these sequences was represented as 3-10 clones in the set that was subjected to sequencing. Further characterization of these transcribed sequences may indicate potential candidates responsible for ADFN. We have discussed the utility of cDNA selection methodology in assembling transcript maps and identifying potential candidates for genetic deafness.

Albinism↗
PubMed2000

Molecular bases of congenital hypopigmentary disorders in humans and oculocutaneous albinism 1 in Japan.

The molecular bases of various types of congenital hypopigmentary disorders have been clarified in the past 10 years. Homozygous gene mutations of enzymes functional in melanogenesis such as tyrosinase, P protein and DHICA oxidase, result in oculocutaneous albinism (OCA) 1, OCA 2, and OCA 3, respectively. The genes responsible for Hermansky-Pudlak syndrome (HPS) and Chediak-Higashi syndrome (CHS) have also recently been isolated and cloned. The transcription factor paired box 3 (PAX3) works at the promoter region of the microphthalmia-associated transcription factor (MITF) gene, and the MITF transcription factor orders the expression of c-kit, which encodes the receptor for stem-cell factor, which in turn stimulates melanoblast migration from the neural tube to the skin in the embryo. Heterozygous mutations of PAX3, MITF, or c-kit genes induce Waardenburg syndrome (WS) 1/3, WS 2 or Piebaldism, respectively. A defect of endothelin-3 or the endothelin-B receptor produces WS 4. In our examination of 26 OCA 1 patients in Japan, all were found to have homozygous or heterozygous tyrosinase gene mutations at codons 77 or 310. Therefore, mutations at codons 77 and 310 are the major ones in Japanese patients with OCA 1. An autosomal dominant pigmentary disease of dyschromatosis symmetrica hereditaria (DSH) is well known in Japan, and is characterized by a mixture of hypo- and hyper-pigmented macules of various sizes on the backs of the hands and feet. The disease gene and its chromosomal localization have not been identified yet. Our trial of linkage analysis and positional cloning to determine the disease gene is presented.

Albinism, Oculocutaneous↗
PubMed2001

The mouse p (pink-eyed dilution) and human P genes, oculocutaneous albinism type 2 (OCA2), and melanosomal pH.

Recessive mutations of the mouse p (pink-eyed dilution) gene lead to hypopigmentation of the eyes, skin, and fur. Mice lacking a functional p protein have pink eyes and light gray fur (if non-agouti) or cream-colored fur (if agouti). The human orthologue is the P protein. Humans lacking a functional P protein have oculocutaneous albinism type 2 (OCA2). Melanocytes from p-deficient mice or OCA2 individuals contain small, minimally pigmented melanosomes. The mouse and human proteins are predicted to have 12 membrane spanning domains and possess significant sequence homology to a number of membrane transport proteins, some of which are involved in the transport of anions. The p protein has been localized to the melanosome membrane. Recently, it has been shown that melanosomes from p protein-deficient melanocytes have an abnormal pH. Melanosomes in cultured melanocytes derived from wild-type mice are typically acidic, whereas melanosomes from p protein-deficient mice are non-acidic. Melanosomes and related endosome-derived organelles (i.e., lysosomes) are thought to have an adenosine triphosphate (ATP)-driven proton pump that helps to generate an acidic lumen. To compensate for the charge of these protons, anions must also be transported to the lumen of the melanosome. In light of these observations, a model of p protein function is presented in which the p protein, together with the ATP-driven proton pump, regulates the pH of the melanosome.

Albinism, Oculocutaneous↗
PubMed2001

Ocular albinism type 1: more than meets the eye.

Ocular albinism type 1 (OA1) is an X-linked recessive disorder characterized by a severe reduction of visual acuity, and hypopigmentation of the retina that leads to nystagmus, strabismus, and photophobia/photodysphoria. Microscopic examination of both retinal pigment epithelium and skin melanocytes in OA1 reveals the presence of macrome-lanosomes, suggesting that the OA1 gene product plays a role in melanosome biogenesis. Studies of mutations identified from OA1 patients and an Oa1 knock-out mouse model further implicate OA1 protein function in the late stage of melanosome development. Because its effects are primarily limited to the eye, OA1 represents an ideal model system to study the relationship between pigmentation and visual development. Based upon sequence homology and biochemical studies, OA1 may represent a novel intracellular G-protein coupled receptor. Understanding the function of OA1 will contribute greatly to our understanding of melanosome biogenesis and the role of pigmentation in visual development.

Albinism, Ocular↗
PubMed2001

Tyrp1 and oculocutaneous albinism type 3.

Tyrosinase-related protein 1 (Tyrp1) is a melanocyte-specific gene product involved in eumelanin synthesis. Mutations in the mouse Tyrp1 gene are associated with brown pelage, and in the human TYRP1 gene with oculocutaneous albinism type 3 (OCA3). In the murine system, Tyrp1 expresses significant dihydroxyindole carboxylic acid oxidase (i.e. DHICA oxidase) activity. However, in humans, TYRP1 is enigmatic in that despite extensive efforts focused on the study of its function, its actual role in the human melanocyte is still unclear. There is mounting evidence demonstrating that in addition to its role in eumelanin synthesis, Tyrp1 is involved in maintaining stability of tyrosinase protein and modulating its catalytic activity. Tyrp1 is also involved in maintenance of melanosome ultrastructure and affects melanocyte proliferation and melanocyte cell death. The current review is an attempt to consolidate our understanding of the role of Tyrp1 in the melanocyte.

Albinism, Oculocutaneous↗
PubMed2002

The etiology of oculocutaneous albinism (OCA) type II: the pink protein modulates the processing and transport of tyrosinase.

Oculocutaneous albinism (OCA) is caused by reduced or deficient melanin pigmentation in the skin, hair, and eyes. OCA has different phenotypes resulting from mutations in distinct pigmentation genes involved in melanogenesis. OCA type 2 (OCA2), the most common form of OCA, is an autosomal recessive disorder caused by mutations in the P gene, the function(s) of which is controversial. In order to elucidate the mechanism(s) involved in OCA2, our group used several antibodies specific for various melanosomal proteins (tyrosinase, Tyrp1, Dct, Pmel17 and HMB45), including a specific set of polyclonal antibodies against the p protein. We used confocal immunohistochemistry to compare the processing and distribution of those melanosomal proteins in wild type (melan-a) and in p mutant (melan-p1) melanocytes. Our results indicate that the melanin content of melan-p1 melanocytes was less than 50% that of wild type melan-a melanocytes. In contrast, the tyrosinase activities were similar in extracts of wild type and p mutant melanocytes. Confocal microscopy studies and pulse-chase analyses showed altered processing and sorting of tyrosinase, which is released from melan-p1 cells to the medium. Processing and sorting of Tyrp1 was also altered to some extent. However, Dct and Pmel17 expression and subcellular localization were similar in melan-a and in melan-p1 melanocytes. In melan-a cells, the p protein showed mainly a perinuclear pattern with some staining in the cytoplasm where some co-localization with HMB45 antibody was observed. These findings suggest that the p protein plays a major role in modulating the intracellular transport of tyrosinase and a minor role for Tyrp1, but is not critically involved in the transport of Dct and Pmel17. This study provides a basis to understand the relationship of the p protein with tyrosinase function and melanin synthesis, and also provides a rational approach to unveil the consequences of P gene mutations in the pathogenesis of OCA2.

Albinism, Oculocutaneous↗
PubMed1999

Ocular albinism: evidence for a defect in an intracellular signal transduction system.

G protein-coupled receptors (GPCRs) participate in the most common signal transduction system at the plasma membrane. The wide distribution of heterotrimeric G proteins in the internal membranes suggests that a similar signalling mechanism might also be used at intracellular locations. We provide here structural evidence that the protein product of the ocular albinism type 1 gene (OA1), a pigment cell-specific integral membrane glycoprotein, represents a novel member of the GPCR superfamily and demonstrate that it binds heterotrimeric G proteins. Moreover, we show that OA1 is not found at the plasma membrane, being instead targeted to specialized intracellular organelles, the melanosomes. Our data suggest that OA1 represents the first example of an exclusively intracellular GPCR and support the hypothesis that GPCR-mediated signal transduction systems also operate at the internal membranes in mammalian cells.

Albinism, Ocular↗
PubMed1980

Two distinct patterns of visual evoked response asymmetry in human albinism.

Results are presented which confirm that in human albinos each cerebral hemisphere receives a predominantly monocular input from the contralateral eye, giving rise to an asymmetry of the visual evoked potential (VEP) to whole-field stimulation which is similar to that for stimulation of the temporal half-field in the same individual. The further finding of two distinct, and in some respects opposite, types of topographical asymmetry raises the possibility that there are two anatomically distinct variants in the retinocortical projection in human albinism, as there are in the Siamese cat.

Albinism↗