Form Of Oculocutaneous Albinism Research Articles

The retinal pigmentation pathway in human albinism: Not so black and white.

Albinism is a pigment disorder affecting eye, skin and/or hair. Patients usually have decreased melanin in affected tissues and suffer from severe visual abnormalities, including foveal hypoplasia and chiasmal misrouting. Combining our data with those of the literature, we propose a single functional genetic retinal signalling pathway that includes all 22 currently known human albinism disease genes. We hypothesise that defects affecting the genesis or function of different intra-cellular organelles, including melanosomes, cause syndromic forms of albinism (Hermansky-Pudlak (HPS) and Chediak-Higashi syndrome (CHS)). We put forward that specific melanosome impairments cause different forms of oculocutaneous albinism (OCA1-8). Further, we incorporate GPR143 that has been implicated in ocular albinism (OA1), characterised by a phenotype limited to the eye. Finally, we include the SLC38A8-associated disorder FHONDA that causes an even more restricted "albinism-related" ocular phenotype with foveal hypoplasia and chiasmal misrouting but without pigmentation defects. We propose the following retinal pigmentation pathway, with increasingly specific genetic and cellular defects causing an increasingly specific ocular phenotype: (HPS1-11/CHS: syndromic forms of albinism)-(OCA1-8: OCA)-(GPR143: OA1)-(SLC38A8: FHONDA). Beyond disease genes involvement, we also evaluate a range of (candidate) regulatory and signalling mechanisms affecting the activity of the pathway in retinal development, retinal pigmentation and albinism. We further suggest that the proposed pigmentation pathway is also involved in other retinal disorders, such as age-related macular degeneration. The hypotheses put forward in this report provide a framework for further systematic studies in albinism and melanin pigmentation disorders.

Hermansky–Pudlak Syndrome Type 6 Accompanied with Bowel Vascular Malformation: Clinical Case

Background. Hermansky–Pudlak syndrome type 6 is rare hereditary disease caused by pathogenic variants in base sequence, deletions, and insertions in the HPS6 gene encoding the transmembrane protein of the same name. This disease occurs with hemorrhagic syndrome, oculocutaneous albinism, and inflammatory bowel diseases (in some cases). The clinical picture of the disease, including the gastrointestinal tract pathology, has not been studied completely due to the syndrome rarity.Clinical case description. We would like to present the description of clinical case of the patient with Hermansky–Pudlak syndrome type 6 accompanied with bowel vascular malformation. The patient diagnosed with “oculocutaneous albinism” at the age of 4.5 has shown recurrent intestinal bleedings, blood hemoglobin concentration decrease to 45 g/l; platelet count, mean platelet volume and platelet distribution width remained within the reference values. Slight decrease of Quick’s value to 68% (normal range 70–120%) was revealed. The study of platelet morphology has revealed a decrease in the number of dense granules: < 3 in 25% platelets, < 6 — in 64%. Ultrasound investigation has revealed signs of vascular malformation in ascending colon: significant changes of diameter (widening) and shape of intestinal wall vessels. Molecular genetic analysis (NGS) has revealed the nucleotide variant c.1133T>G (p.Leu378Arg) in homozygous state in the HPS6 gene. The same variant in homozygous state was revealed in the younger proband sister who also had vascular changes in the ascending colon wall.Conclusion. Differential diagnosis of Germanic–Pudlak syndrome type 6 should be performed with other types of this syndrome as well as with syndrome and non-syndrome forms of oculocutaneous albinism. Molecular genetic confirmation of the diagnosis is suggested via massive parallel sequencing (NGS) methods (exome sequencing included) due to the rarity of Hermansky–Pudlak syndrome.

Biophysical Compatibility of a Heterotrimeric Tyrosinase-TYRP1-TYRP2 Metalloenzyme Complex.

Tyrosinase (TYR) is a copper-containing monooxygenase central to the function of melanocytes. Alterations in its expression or activity contribute to variations in skin, hair and eye color, and underlie a variety of pathogenic pigmentary phenotypes, including several forms of oculocutaneous albinism (OCA). Many of these phenotypes are linked to individual missense mutations causing single nucleotide variants and polymorphisms (SNVs) in TYR. We previously showed that two TYR homologues, TYRP1 and TYRP2, modulate TYR activity and stabilize the TYR protein. Accordingly, to investigate whether TYR, TYRP1, and TYRP2 are biophysically compatible with various heterocomplexes, we computationally docked a high-quality 3D model of TYR to the crystal structure of TYRP1 and to a high-quality 3D model of TYRP2. Remarkably, the resulting TYR-TYRP1 heterodimer was complementary in structure and energy with the TYR-TYRP2 heterodimer, with TYRP1 and TYRP2 docking to different adjacent surfaces on TYR that apposed a third realistic protein interface between TYRP1-TYRP2. Hence, the 3D models are compatible with a heterotrimeric TYR-TYRP1-TYRP2 complex. In addition, this heterotrimeric TYR-TYRP1-TYRP2 positioned the C-terminus of each folded enzymatic domain in an ideal position to allow their C-terminal transmembrane helices to form a putative membrane embedded three-helix bundle. Finally, pathogenic TYR mutations causing OCA1A, which also destabilize TYR biochemically, cluster on an unoccupied protein interface at the periphery of the heterotrimeric complex, suggesting that this may be a docking site for OCA2, an anion channel. Pathogenic OCA2 mutations result in similar phenotypes to those produced by OCA1A TYR mutations. While this complex may be difficult to detect in vitro, due to the complex environment of the vertebrate cellular membranous system, our results support the existence of a heterotrimeric complex in melanogenesis.

Oculocutaneous and ocular albinism

Albinism can be divided into oculocutaneous albinism (OCA) and ocular albinism (OA). In the differential diagnostics these can be distinguished from rarer syndromes with partial albinism, which are frequently associated with susceptibility to infections and neurological symptoms. The OCA is an autosomal recessive inherited disease of melanin biosynthesis, which leads to complete or partial loss of melanin in the skin, hair follicles and eyes. Of the seven currently known subtypes (OCA 1-7), four are well-characterized (OCA 1-4). These are based on gene mutations, which code for tyrosinase, a key enzyme in melanin synthesis and for further proteins. These play an important role in the catalytic activity of tyrosinase and the structure and function of melanosomes. In the presence of these subtypes, the clinical symptoms and the course of the disease show a pronounced variability, especially in the type and extent of pigmentation of the skin and hair as well as the severity of eye involvement, which makes the phenotypic classification difficult. Treatment priorities are a consistent protection from UV light for prophylaxis against skin cancer and regular preventive investigations. The ocular alterations typical for albinism necessitate timely diagnostics and care by institutions specialized in ophthalmology. Novel strategies for systemic treatment of subtypes of albinism are in preclinical testing. The OA without skin involvement shows X‑linked inheritance, is much rarer and is characterized by reduced pigmentation of the retina and iris, nystagmus and macular hypoplasia, sometimes with substantial loss of visual acuity. The typical ocular symptoms of OA can be manifested to a varying extent in all forms of OCA.

Biology and genetics of oculocutaneous albinism and vitiligo – common pigmentation disorders in southern Africa

Pigmentation disorders span the genetic spectrum from single-gene autosomal recessive disorders such as oculocutaneous albinism (OCA), the autosomal dominant disorder piebaldism to X-linked ocular albinism and multifactorial vitiligo. OCA connotes a group of disorders that result in hypopigmented skin due to decreased melanin production in melanocytes and loss of visual acuity. There are four non-syndromic forms, OCA1-4, which are classified based on the gene that is mutated (tyrosinase, OCA2, tyrosinase-related protein 1 and SLC45A2, respectively). Despite the fact that multiple genes account for the various forms of OCA, the phenotypes of all four forms result from disruption in the maturation and trafficking of the enzyme tyrosinase. OCA2 is the most prevalent autosomal recessive disorder among southern African blacks, affecting 1/3 900 individuals; while OCA3, although rare, is most prevalent in southern Africa. Another common pigmentation disorder in southern Africa is vitiligo, which affects 1 - 2% of people worldwide. Vitiligo is a complex, acquired disorder in which melanocytes are destroyed due to an autoimmune response. The aetiology underlying this disorder is poorly understood, although recent genetic association studies have begun to shed light on the contributing factors. Pigmentation disorders have significant psychosocial implications and co-morbidities, yet therapies are still lacking. Recent progress in our understanding of the pathobiology of both albinism and vitiligo may herald novel treatment strategies for these disorders.

TYPES OF ALBINISM IN THE BLACK SOUTHERN AFRICA POPULATION.

Oculocutaneous albinism (OCA) is the most common inherited disorder in Southern African blacks and several types have been described. Molecular techniques, where available, can be used to confirm a clinical diagnosis and the type of OCA, if necessary, and for prenatal diagnosis. To investigate and classify the different types of albinism commonly found and to determine the clinical implications for each type. A descriptive survey. Gauteng province, South Africa, and Lesotho. Three groups of subjects with OCA (96 from a genetics clinic, 62 from a dermatology clinic, and 31 from community surveys) from the black African population participated. Subjects underwent clinical and/or dermatological examinations and were then classified according to type of OCA. Four forms of OCA were identified: most (82%) subjects had OCA2 (a tyrosinase- positive type) with three sub-types: those without large freckles (ephelides) on exposed areas (named OCA 2a in this study), those with such freckles (named OCA 2b), and those with brown albinism (BOCA); the remainder had red/rufous albinism, ROCA (OCA 3). The four forms could be distinguished from each other clinically without using molecular genetic testing. The most common types of albinism found in the black population of Southern Africa are OCA2 and OCA3. Given the high prevalence of the disorder, together with the high risk of skin cancer, and the recent persecution of affected individuals in certain East African countries, these findings and their clinical implications have significance in terms of both education and awareness for health professionals and lay people caring for those with albinism.

The Genetics of Human Pigmentary Disorders

Interest in the genetics of human and animal pigmentation is longstanding. Variation in human pigmentary form— of skin, hair, and eyes—is one of the most striking polymorphic human traits. Ever since Charles Darwin, biologists have been asking how and why did Nature fashion men so differently across the earth? Moving beyond what we might consider natural physiological variation in skin color to the pathological, human pigmentary disorders such as albinism is often clinically striking. Therefore, some syndromes were described early in modern medical history, and what we would now recognize as modern genetic insights into their nature were present almost as early as the rediscovery of Gregor Mendel’s work just over a century ago. The two decades spanning the start of the twenty-first century have been extraordinarily productive for those interested in human pigment genetics. Of course, the influence and power of what was once called the ‘‘New Genetics’’ has been felt across much of modern biomedicine, but to this skin-watcher, at least, few areas of study have seen such progress with apparently so modest an investment in funding. Recounting the story of this advance is necessary not merely to pay homage to those who laid the foundations that later successes were built on, but also as a lesson for those working in other fields of biomedicine where the problems often appear less tractable. The development of the mouse fancy, and the subsequent institutionalization of this in the twentieth century, provided a fertile resource for those keen to understand mammalian biology (Lamoreux et al., 2010). Interest in this topic, however, was not limited to those, such as skin biologists or dermatologists, whose interests are—professionally speaking—skin deep, but included those far-sighted biologists who recognized that the astonishing diversity of murine coat color mutants offered a way to address the general problem of how genes work. When technological advances in molecular genetics made mammalian gene identification almost routine, the resource of the mouse fancy offered an unrivaled experimental model system both for those interested in human pigmentation and for those whose goals were more general.

Clinico-epidemiologic features of oculocutaneous albinism in northeast section of Cairo – Egypt

Background Oculocutaneous albinism (OCA) is a genetically heterogeneous group of disorders characterized by the absence or reduced pigmentation of the skin, hair and eyes. To assess the clinico-epidemiologic features of different forms of OCA among Egyptian patients, we performed a retrospective study to determine the frequency, types, clinical presentation and associated genomic errors in albino patients and their relatives consulting the Genetics Clinic, Pediatric Hospital, Ain Shams University, Cairo, Egypt. Methods We used the outpatients index files to identify diagnosed cases of albinism referred from the dermatologic and ophthalmologic departments with different genodermatoses over 43 year period. We used specifically designed data collection protocol forms to extract epidemiological and clinical data from the patients medical records. These were entered into a computer database and analyzed using standard statistical software. Results The occurrence rate of albinism in our study was 20.4% of genodermatoses patients and 1 per 5843 patients attending the Pediatric hospital. Consanguineous marriage was reported among parents of 66.37% of patients and positive family history was reported in 46.01% of patients. Complete OCA was detected in 48.59% of patients, partial albinism in 41.59% of patients and syndromic albinism was detected in 7.96%. Associated genomic errors were detected in 36.28% of our albino patients and seventy one multiple mutant genomic errors were defined among relatives of thirty seven index families of oculocutaneous albinism patients. Conclusion To the best of our knowledge, this preliminary study is the first report of its kind from Egypt. The high rate of parental consanguinity among the parents of our Egyptian albino patients may account for the frequency of this genodermatosis in Egypt.

Proteomic analysis of platelet alpha-granules using mass spectrometry.

Platelets have three major types of secretory organelles: lysosomes, dense granules, and alpha-granules. alpha-Granules contain several adhesive proteins involved in hemostasis, as well as glycoproteins involved in inflammation, wound healing, and cell-matrix interactions. This article represents the first effort to define the platelet alpha-granule proteome using mass spectrometry (MS). We prepared a subcellular fraction enriched in intact alpha-granules from human platelets using sucrose gradient ultracentrifugation. alpha-Granule proteins were separated and identified using sodium dodecylsulfate polyacrylamide gel electrophoresis and liquid chromatography-tandem MS. In the sucrose fraction enriched in alpha-granules, we identified 284 non-redundant proteins, 44 of which appear to be new alpha-granule proteins, on the basis of a literature review. Immunoelectron microscopy confirmed the presence of Scamp2, APLP2, ESAM and LAMA5 in platelet alpha-granules for the first time. We identified 65% of the same proteins that were detected in the platelet releasate (J. A. Coppinger et al. [Blood 2004;103: 2096-104]) as well as additional soluble and membrane proteins. Our method provides a suitable tool for analyzing the granule proteome of patients with storage pool deficiencies.

A New Form of Oculocutaneous Albinism, OCA4

Oculocutaneous albinism (OCA) is a complex genetic disease with great clinical heterogeneity. Four different types of OCA have been reported to date (OCA1, OCA2, OCA3, and OCA4). OCA4 was firstly reported in a Turkish OCA patient. The gene responsible for OCA4 is the human homologue of the mouse underwhite (uw) gene, which encodes the mem-brane-associated transporter protein (MATP). MATP gene is located on chromosome 5p13.3 and is divided into 7 exons and 6 introns. MATP gene is transcriptionally modulated by MITF, and encodes a protein of 530 amino acids. There are at least 18 pathologic mutations and 8 non-pathologic polymorphisms have been found.

Tyrosinase processing and intracellular trafficking is disrupted in mouse primary melanocytes carrying the underwhite (uw) mutation. A model for oculocutaneous albinism (OCA) type 4.

Oculocutaneous albinism (OCA) type 4 is a newly identified human autosomal recessive hypopigmentary disorder that disrupts pigmentation in the skin, hair and eyes. Three other forms of OCA have been previously characterized, each resulting from the aberrant processing and/or sorting of tyrosinase, the enzyme critical to pigment production in mammals. The disruption of tyrosinase trafficking occurs at the level of the endoplasmic reticulum (ER) in OCA1 and OCA3, but at the post-Golgi level in OCA2. The gene responsible for OCA4 is the human homologue of the mouse underwhite (uw) gene, which encodes the membrane-associated transporter protein (MATP). To characterize OCA4, we investigated the processing and sorting of melanogenic proteins in primary melanocytes derived from uw/uw mice and from wild-type mice. OCA4 melanocytes were found to be constantly secreted into the medium dark vesicles that contain tyrosinase and two other melanogenic enzymes, Tyrp1 (tyrosinase-related protein 1) and Dct (DOPAchrome tautomerase); this secretory process is not seen in wild-type melanocytes. Although tyrosinase was synthesized at comparable rates in wild-type and in uw-mutant melanocytes, tyrosinase activity in uw-mutant melanocytes was only about 20% of that found in wild-type melanocytes, and was enriched only about threefold in melanosomes compared with the ninefold enrichment in wild-type melanocytes. OCA4 melanocytes showed a marked difference from wild-type melanocytes in that tyrosinase was abnormally secreted from the cells, a process similar to that seen in OCA2 melanocytes, which results from a mutation of the pink-eyed dilution (P) gene. The P protein and MATP have 12 transmembrane regions and are predicted to function as transporters. Ultrastructural analysis shows that the vesicles secreted from OCA4 melanocytes are mostly early stage melanosomes. Taken together, our results show that in OCA4 melanocytes, tyrosinase processing and intracellular trafficking to the melanosome is disrupted and the enzyme is abnormally secreted from the cells in immature melanosomes, which disrupts the normal maturation process of those organelles. This mechanism explains the hypopigmentary phenotype of these cells and provides new insights into the involvement of transporters in the normal physiology of melanocytes.

Mutations in the Human Orthologue of the Mouse underwhite Gene ( uw) Underlie a New Form of Oculocutaneous Albinism, OCA4

Oculocutaneous albinism (OCA) affects approximately 1/20,000 people worldwide. All forms of OCA exhibit generalized hypopigmentation. Reduced pigmentation during eye development results in misrouting of the optic nerves, nystagmus, alternating strabismus, and reduced visual acuity. Loss of pigmentation in the skin leads to an increased risk for skin cancer. Two common forms and one infrequent form of OCA have been described. OCA1 (MIM 203100) is associated with mutations of the TYR gene encoding tyrosinase (the rate-limiting enzyme in the production of melanin pigment) and accounts for approximately 40% of OCA worldwide. OCA2 (MIM 203200), the most common form of OCA, is associated with mutations of the P gene and accounts for approximately 50% of OCA worldwide. OCA3 (MIM 203290), a rare form of OCA and also known as "rufous/red albinism," is associated with mutations in TYRP1 (encoding tyrosinase-related protein 1). Analysis of the TYR and P genes in patients with OCA suggests that other genes may be associated with OCA. We have identified the mouse underwhite gene (uw) and its human orthologue, which underlies a new form of human OCA, termed "OCA4." The encoded protein, MATP (for "membrane-associated transporter protein") is predicted to span the membrane 12 times and likely functions as a transporter.

Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome) [correction of (Hennansky-Pudlak)

<b>NEW ENGLAND JOURNAL OF MEDICINE</b> <b>Genetic Defects and Clinical Characteristics of Patients With a Form of Oculocutaneous Albinism (Hennansky-Pudlak Syndrome)</b> <i>William A. Gahl, M.D., Ph.D., Mark Brantly, M.D., Muriel I. Kaiser-Kupfer, M.D., Fumino Iwata, M.D., Senator Hazelwood, B.S., Vorasuk Shotelersuk, M.D., Lynn F. Duffy, M.D., Ernest M. Kuehl, James Troendle, Ph.D., and Isa Bernardini, M.Ed.</i> <i>Background</i>Hermansky–Pudlak syndrome is characterized by oculocutaneous albinism, a storage-pool deficiency, and lysosomal accumulation of ceroid lipofuscin, which causes pulmonary fibrosis and granulomatous colitis in some areas. All identified affected patients in northwest Puerto Rico are homozygous for a 16-bp duplication in exon 15 of a recently cloned gene,<i>HPS</i>. We compared the clinical and laboratory characteristics of these patients with those of patients without the 16-bp duplication. <i>Methods</i>Forty-nine patients—27 Puerto Ricans and 22 patients from the mainland United States who were not of Puerto Rican descent—were given a diagnosis on the basis of albinism and the absence of platelet dense bodies. We used the polymerase chain reaction to determine which patients carried the 16-bp duplication. <i>Results</i>Twenty-five of the Puerto Rican patients were homozygous for the 16-bp duplication, whereas none of the non–Puerto Rican patients carried this mutation. Like the patients without the duplication, the patients with the 16-bp duplication had a broad variation in pigmentation. Nine of 16 adults with the duplication, but none of the 10 without it, had a diffusing capacity for carbon monoxide that was less than 80 percent of the predicted value. High-resolution computed tomography in 12 patients with the 16-bp duplication revealed minimal fibrosis in 8, moderate fibrosis in 1, severe fibrosis in 1, and no fibrosis in 2. Computed tomography in eight patients without the duplication revealed minimal fibrosis in three and no fibrosis in the rest. Inflammatory bowel disease developed in eight patients (four in each group) between 3 and 25 years of age. <i>Conclusions</i>The 16-bp duplication in exon 15 of<i>HPS</i>, which we found only in Puerto Rican patients, is associated with a broad range of pigmentation and an increased risk of restrictive lung disease in adults. <i>1998;338:1258-1264.</i>

Human tyrosinase gene, mapped to chromosome 11 (q14 → q21), defines second region of homology with mouse chromosome 7

The enzyme tyrosinase (monophenol, l-dopa:oxygen oxidoreductase; EC 1.14.18.1) catalyzes the first two steps in the conversion of tyrosine to melanin, the major pigment found in melanocytes. Some forms of oculocutaneous albinism, characterized by the absence of melanin in skin and eyes and by a deficiency of tyrosinase activity, may result from mutations in the tyrosinase structural gene. A recently isolated human tyrosinase cDNA was used to map the human tyrosinase locus ( TYR) to chromosome 11, region q14 → q21, by Southern blot analysis of somatic cell hybrid DNA and by in situ chromosomal hybridization. A second site of tyrosinase-related sequences was detected on the short arm of chromosome 11 near the centromere (p11.2 → cen). Furthermore, we have confirmed the localization of the tyrosinase gene in the mouse at or near the c locus on chromosome 7. Comparison of the genetic maps of human chromosome 11 and mouse chromosome 7 leads to hypotheses regarding the evolution of human chromosome 11.

Hermansky-Pudlak syndrome: Pulmonary manifestations of a ceroid storage disorder

The Hermansky-Pudlak syndrome is a form of oculocutaneous albinism, characterized by a qualitative platelet defect and deposition of ceroid-like material throughout the reticuloendothelial system. During a 16 month period five patients with Hermansky-Pudlak syndrome presented with symptoms, chest films and pulmonary function studies consistent with restrictive pulmonary disease. In two patients, lung biopsies revealed diffuse interstitial fibrosis. However, light and electron microscopy demonstrated ceroid-like material within alveolar macrophages. In addition, two patients presented with inflammatory bowel disease with deposition of ceroid-like material in the colon. This disorder appears to be more common than is currently recognized and should be considered in the differential diagnosis of diffuse interstitial pulmonary disease and inflammatory bowel disease. A relationship between the deposition of ceroid-like material and pulmonary fibrosis is discussed in light of recent research concerning inflammatory processes. In view of the serious pulmonary, gastrointestinal and hematologic consequences of this syndrome, there is a need for genetic counseling of these patients.

Albinism

There are seven forms of oculo-cutaneous albinism, which are all autosomal recessive: three are tyrosinase-negative (complete oculo-cutaneous albinism, Amish albinism, Hermansky-Pudlak syndrome) and four are tyrosinase-positive (incomplete oculo-cutaneous albinism, Chediak-Higashi syndrome, Cross syndrome, Bergsma's albinism). There are three forms of sex-linked albinism: ocular albinism, which is intermediary sex-linked, François-De Rouck syndrome and Ziprkowski syndrome, which show a generalized albinism and are recessive sex-linked. There are two principal forms of cutaneous albinism, one without deafness and the other with deafness (Waardenburg-Klein syndrome).