The Experts below are selected from a list of 1803 Experts worldwide ranked by ideXlab platform
Richard A King - One of the best experts on this subject based on the ideXlab platform.
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posterior staphyloma in Oculocutaneous Albinism another possible cause of reduced visual acuity
Journal of Aapos, 2015Co-Authors: Lisa A Schimmenti, Murray H Brilliant, Richard A King, Cheri Schoonveld, Jennifer L. Anderson, Gail C SummersAbstract:Posterior staphyloma is typically associated with myopic degeneration and has not been recognized as a cause of reduced visual acuity in Albinism. We report 3 cases of posterior staphyloma, each with Oculocutaneous Albinism (OCA) defined by phenotype and genotype. Two cases are biological sisters with OCA type 2; one was myopic and the other was hyperopic. The third case involves a man with OCA associated with Hermansky-Pudlak syndrome (HPS-5). Staphyloma may be another cause of reduced visual acuity in Albinism, particularly with increasing age. It may occur in association with myopia or hyperopia.
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p gene mutations associated with Oculocutaneous Albinism type ii oca2
Human Mutation, 2005Co-Authors: William S. Oetting, Marcia J Brott, Sarah Savage Garrett, Richard A KingAbstract:Oculocutaneous Albinism type II (OCA2) is the most common form of Albinism in humans. OCA2 has been previously associated with mutations of the P gene, the human homologue to the murine pink-eyed dilution gene. The P gene encodes a 110 kDa protein containing 12 potential membrane spanning domains and is associated with melanosomal membranes. The specific function of the P protein is currently unknown but is thought to be involved in tyrosinase processing and transport. We report nine novel mutations in the P gene associated with OCA2. These include two missense mutations, c.1938A>C (p.Ile646Val) and c.1556T>C (p.Val519Ala); one nonsense mutation c.612G>A (p.Trp204X); five frameshift mutations: c.2372underscore;2373delTC, c.1555delG, c.1938underscore;1939insC, c.2050delT, and c.1045underscore;1046delAT; and a splice site mutation c.1951+1G>A. We also report 12 novel polymorphisms including one amino acid substitution, c.2365underscore;2366GC>CA (p.Ala789Glu). At present, there is no functional assay to determine if a mutation is truly pathogenic. The presence of numerous polymorphisms of the P gene in the coding region, several of which result in amino acid substitutions, makes molecular diagnosis problematic. To ensure accurate molecular diagnosis, further mutational analysis will be necessary to produce a comprehensive list of mutations associated with OCA2. This information will also help define the critical functional domains of the P protein. Mutations associated with OCA2 can be found in the Albinism Database (http://Albinismdb.med.umn.edu). © 2005 Wiley-Liss, Inc.
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p gene mutations associated with Oculocutaneous Albinism type ii oca2
Human Mutation, 2005Co-Authors: William S. Oetting, Marcia J Brott, Sarah Savage Garrett, Richard A KingAbstract:Oculocutaneous Albinism type II (OCA2) is the most common form of Albinism in humans. OCA2 has been previously associated with mutations of the P gene, the human homologue to the murine pink-eyed dilution gene. The P gene encodes a 110 kDa protein containing 12 potential membrane spanning domains and is associated with melanosomal membranes. The specific function of the P protein is currently unknown but is thought to be involved in tyrosinase processing and transport. We report nine novel mutations in the P gene associated with OCA2. These include two missense mutations, c.1938A>C (p.Ile646Val) and c.1556T>C (p.Val519Ala); one nonsense mutation c.612G>A (p.Trp204X); five frameshift mutations: c.2372_2373delTC, c.1555delG, c.1938_1939insC, c.2050delT, and c.1045_1046delAT; and a splice site mutation c.1951+1G>A. We also report 12 novel polymorphisms including one amino acid substitution, c.2365_2366GC>CA (p.Ala789Glu). At present, there is no functional assay to determine if a mutation is truly pathogenic. The presence of numerous polymorphisms of the P gene in the coding region, several of which result in amino acid substitutions, makes molecular diagnosis problematic. To ensure accurate molecular diagnosis, further mutational analysis will be necessary to produce a comprehensive list of mutations associated with OCA2. This information will also help define the critical functional domains of the P protein. Mutations associated with OCA2 can be found in the Albinism Database (http://Albinismdb.med.umn.edu).
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tyrosinase gene mutations in Oculocutaneous Albinism 1 oca1 definition of the phenotype
Human Genetics, 2003Co-Authors: Richard A King, Gail C Summers, James P. Fryer, Jacy Pietsch, Sarah Savage, Marcia J Brott, Isabelle Russelleggitt, William S. OettingAbstract:Oculocutaneous Albinism (OCA) is a common human genetic condition resulting from mutations in at least twelve different genes. OCA1 results from mutations of the tyrosinase gene and presents with the life-long absence of melanin pigment after birth (OCA1A) or with the development of minimal-to-moderate amounts of cutaneous and ocular pigment (OCA1B). Other types of OCA have variable amounts of cutaneous and ocular pigment. We hypothesized that white hair at birth indicates OCA1 and tested this in a sample of 120 probands with OCA and white hair at birth. We found that 102 (85%) of the probands had OCA1 with one or two identifiable tyrosinase gene mutations, with 169 (83%) of the 204 OCA1 tyrosinase gene alleles having identifiable mutations and 35 (17%) having no identifiable change in the coding, splice junction, or proximal promoter regions of the gene. The inability to identify the mutation was more common with OCA1B (24/35, 69%) than with OCA1A (11/35, 31%) alleles. Seven probands with no tyrosinase gene mutations were found to have OCA2 with one or two P gene mutations, and in eleven, no mutations were detected in either gene. We conclude that (1) the presence of white hair at birth is a useful clinical tool suggesting OCA1 in a child or adult with OCA, although OCA2 may also have this presentation; (2) the molecular analysis of the tyrosinase and P genes are necessary for precise diagnosis; and (3) the presence of alleles without identifiable mutations of the tyrosinase gene, particularly in OCA1B, suggests that more complex mutation mechanisms of this gene are common in OCA.
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mc1r mutations modify the classic phenotype of Oculocutaneous Albinism type 2 oca2
American Journal of Human Genetics, 2003Co-Authors: Richard A King, Gail C Summers, James P. Fryer, Jacy Pietsch, Sarah Savage, Marcia J Brott, R Willaert, Ramona M Schmidt, William S. OettingAbstract:The heterogeneous group of disorders known as Oculocutaneous Albinism (OCA) shares cutaneous and ocular hypopigmentation associated with common developmental abnormalities of the eye. Mutations of at least 11 loci produce this phenotype. The majority of affected individuals develop some cutaneous melanin; this is predominantly seen as yellow/blond hair, whereas fewer have brown hair. The OCA phenotype is dependent on the constitutional pigmentation background of the family, with more OCA pigmentation found in families with darker constitutional pigmentation, which indicates that other genes may modify the OCA phenotype. Sequence variation in the melanocortin-1 receptor (MC1R) gene is associated with red hair in the normal population, but red hair is unusual in OCA. We identified eight probands with OCA who had red hair at birth. Mutations in the P gene were responsible for classic phenotype of Oculocutaneous Albinism type 2 (OCA2) in all eight, and mutations in the MC1R gene were responsible for the red (rather than yellow/blond) hair in the six of eight who continued to have red hair after birth. This is the first demonstration of a gene modifying the OCA phenotype in humans.
William S. Oetting - One of the best experts on this subject based on the ideXlab platform.
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p gene mutations associated with Oculocutaneous Albinism type ii oca2
Human Mutation, 2005Co-Authors: William S. Oetting, Marcia J Brott, Sarah Savage Garrett, Richard A KingAbstract:Oculocutaneous Albinism type II (OCA2) is the most common form of Albinism in humans. OCA2 has been previously associated with mutations of the P gene, the human homologue to the murine pink-eyed dilution gene. The P gene encodes a 110 kDa protein containing 12 potential membrane spanning domains and is associated with melanosomal membranes. The specific function of the P protein is currently unknown but is thought to be involved in tyrosinase processing and transport. We report nine novel mutations in the P gene associated with OCA2. These include two missense mutations, c.1938A>C (p.Ile646Val) and c.1556T>C (p.Val519Ala); one nonsense mutation c.612G>A (p.Trp204X); five frameshift mutations: c.2372underscore;2373delTC, c.1555delG, c.1938underscore;1939insC, c.2050delT, and c.1045underscore;1046delAT; and a splice site mutation c.1951+1G>A. We also report 12 novel polymorphisms including one amino acid substitution, c.2365underscore;2366GC>CA (p.Ala789Glu). At present, there is no functional assay to determine if a mutation is truly pathogenic. The presence of numerous polymorphisms of the P gene in the coding region, several of which result in amino acid substitutions, makes molecular diagnosis problematic. To ensure accurate molecular diagnosis, further mutational analysis will be necessary to produce a comprehensive list of mutations associated with OCA2. This information will also help define the critical functional domains of the P protein. Mutations associated with OCA2 can be found in the Albinism Database (http://Albinismdb.med.umn.edu). © 2005 Wiley-Liss, Inc.
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p gene mutations associated with Oculocutaneous Albinism type ii oca2
Human Mutation, 2005Co-Authors: William S. Oetting, Marcia J Brott, Sarah Savage Garrett, Richard A KingAbstract:Oculocutaneous Albinism type II (OCA2) is the most common form of Albinism in humans. OCA2 has been previously associated with mutations of the P gene, the human homologue to the murine pink-eyed dilution gene. The P gene encodes a 110 kDa protein containing 12 potential membrane spanning domains and is associated with melanosomal membranes. The specific function of the P protein is currently unknown but is thought to be involved in tyrosinase processing and transport. We report nine novel mutations in the P gene associated with OCA2. These include two missense mutations, c.1938A>C (p.Ile646Val) and c.1556T>C (p.Val519Ala); one nonsense mutation c.612G>A (p.Trp204X); five frameshift mutations: c.2372_2373delTC, c.1555delG, c.1938_1939insC, c.2050delT, and c.1045_1046delAT; and a splice site mutation c.1951+1G>A. We also report 12 novel polymorphisms including one amino acid substitution, c.2365_2366GC>CA (p.Ala789Glu). At present, there is no functional assay to determine if a mutation is truly pathogenic. The presence of numerous polymorphisms of the P gene in the coding region, several of which result in amino acid substitutions, makes molecular diagnosis problematic. To ensure accurate molecular diagnosis, further mutational analysis will be necessary to produce a comprehensive list of mutations associated with OCA2. This information will also help define the critical functional domains of the P protein. Mutations associated with OCA2 can be found in the Albinism Database (http://Albinismdb.med.umn.edu).
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tyrosinase gene mutations in Oculocutaneous Albinism 1 oca1 definition of the phenotype
Human Genetics, 2003Co-Authors: Richard A King, Gail C Summers, James P. Fryer, Jacy Pietsch, Sarah Savage, Marcia J Brott, Isabelle Russelleggitt, William S. OettingAbstract:Oculocutaneous Albinism (OCA) is a common human genetic condition resulting from mutations in at least twelve different genes. OCA1 results from mutations of the tyrosinase gene and presents with the life-long absence of melanin pigment after birth (OCA1A) or with the development of minimal-to-moderate amounts of cutaneous and ocular pigment (OCA1B). Other types of OCA have variable amounts of cutaneous and ocular pigment. We hypothesized that white hair at birth indicates OCA1 and tested this in a sample of 120 probands with OCA and white hair at birth. We found that 102 (85%) of the probands had OCA1 with one or two identifiable tyrosinase gene mutations, with 169 (83%) of the 204 OCA1 tyrosinase gene alleles having identifiable mutations and 35 (17%) having no identifiable change in the coding, splice junction, or proximal promoter regions of the gene. The inability to identify the mutation was more common with OCA1B (24/35, 69%) than with OCA1A (11/35, 31%) alleles. Seven probands with no tyrosinase gene mutations were found to have OCA2 with one or two P gene mutations, and in eleven, no mutations were detected in either gene. We conclude that (1) the presence of white hair at birth is a useful clinical tool suggesting OCA1 in a child or adult with OCA, although OCA2 may also have this presentation; (2) the molecular analysis of the tyrosinase and P genes are necessary for precise diagnosis; and (3) the presence of alleles without identifiable mutations of the tyrosinase gene, particularly in OCA1B, suggests that more complex mutation mechanisms of this gene are common in OCA.
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mc1r mutations modify the classic phenotype of Oculocutaneous Albinism type 2 oca2
American Journal of Human Genetics, 2003Co-Authors: Richard A King, Gail C Summers, James P. Fryer, Jacy Pietsch, Sarah Savage, Marcia J Brott, R Willaert, Ramona M Schmidt, William S. OettingAbstract:The heterogeneous group of disorders known as Oculocutaneous Albinism (OCA) shares cutaneous and ocular hypopigmentation associated with common developmental abnormalities of the eye. Mutations of at least 11 loci produce this phenotype. The majority of affected individuals develop some cutaneous melanin; this is predominantly seen as yellow/blond hair, whereas fewer have brown hair. The OCA phenotype is dependent on the constitutional pigmentation background of the family, with more OCA pigmentation found in families with darker constitutional pigmentation, which indicates that other genes may modify the OCA phenotype. Sequence variation in the melanocortin-1 receptor (MC1R) gene is associated with red hair in the normal population, but red hair is unusual in OCA. We identified eight probands with OCA who had red hair at birth. Mutations in the P gene were responsible for classic phenotype of Oculocutaneous Albinism type 2 (OCA2) in all eight, and mutations in the MC1R gene were responsible for the red (rather than yellow/blond) hair in the six of eight who continued to have red hair after birth. This is the first demonstration of a gene modifying the OCA phenotype in humans.
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Oculocutaneous Albinism type 1: the last 100 years.
Pigment Cell Research, 2003Co-Authors: William S. Oetting, James P. Fryer, Sabitha Shriram, Richard A KingAbstract: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.
Tamio Suzuki - One of the best experts on this subject based on the ideXlab platform.
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genetics of non syndromic and syndromic Oculocutaneous Albinism in human and mouse
Pigment Cell & Melanoma Research, 2021Co-Authors: Almudena Fernandez, Tamio Suzuki, Masahiro Hayashi, Gema Garrido, Andrea Montero, Ana Guardia, Lluis MontoliuAbstract:Oculocutaneous Albinism (OCA) is the most frequent presentation of Albinism, a heterogeneous rare genetic condition generally associated with variable alterations in pigmentation and with a profound visual impairment. There are non-syndromic and syndromic types of OCA, depending on whether the gene product affected impairs essentially the function of melanosomes or, in addition, that of other lysosome-related organelles (LROs), respectively. Syndromic OCA can be more severe and associated with additional systemic consequences, beyond pigmentation and vision alterations. In addition to OCA, Albinism can also be presented without obvious skin and hair pigmentation alterations, in ocular Albinism (OA), and a related genetic condition known as foveal hypoplasia, optic nerve decussation defects, and anterior segment dysgenesis (FHONDA). In this review, we will focus only in the genetics of skin pigmentation in OCA, both in human and mouse, updating our current knowledge on this subject.
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the molecular basis of chemical chaperone therapy for Oculocutaneous Albinism type 1a
Journal of Investigative Dermatology, 2019Co-Authors: Ayako Teramae, Yui Kobayashi, Hiroyuki Kunimoto, Koichi Nakajima, Tamio Suzuki, Daisuke Tsuruta, Kazuyoshi FukaiAbstract:Oculocutaneous Albinism (OCA) is an autosomal recessive disease characterized by the reduction or complete lack of melanin pigment in the skin, hair, and eyes. No effective treatment for OCA is available at present. OCA type 1 is caused by mutations that disrupt the function of tyrosinase (TYR), the rate-limiting enzyme of melanin synthesis. Recently, it was shown that tyrosinase in some patients with OCA type 1 mutation is retained in the endoplasmic reticulum and that its catalytic activity is lost, a phenomenon known as endoplasmic reticulum retention. However, to our knowledge, the intracellular localization of tyrosinase in Japanese patients with OCA type 1 missense mutations has not been reported. In this study, we first investigated the intracellular localization of Japanese OCA type 1A missense mutant tyrosinases using Western blotting and immunohistochemical staining. R77Q, R239W, D383N, and P431L mutant tyrosinases were retained in the endoplasmic reticulum, and H211Y mutant tyrosinase was partially transported to the Golgi apparatus. Second, we explored the possibility of chemical chaperone therapy for Japanese patients with OCA type 1A missense mutations and found that HeLa cells expressing P431L mutant tyrosinase have restored tyrosinase activity after treatment with a low-dose tyrosinase inhibitor, as a chemical chaperone, in a dose-dependent manner. These results provide the basis for a possible chemical chaperone therapy to recover tyrosinase activities in patients with OCA type 1A patients.
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Oculocutaneous Albinism type 3: a Japanese girl with novel mutations in TYRP1 gene.
Journal of Dermatological Science, 2011Co-Authors: Makiko Yamada, Masahiro Hayashi, Keisuke Sakai, Yutaka Hozumi, Yuko Abe, Masakazu Kawaguchi, Hironobu Ihn, Tamio SuzukiAbstract:Abstract Background Oculocutaneous Albinism (OCA) type 3 caused by mutations of the TYRP1 gene is an autosomal recessive disorder of pigmentation characterized by reduced biosynthesis of melanin pigment in the skin, hair, and eye. The clinical phenotype has been reported as mild in Caucasian OCA3 patients. Objective We had the opportunity to examine a Japanese girl with OCA3 and investigated activity of TYRP1 protein derived from the mutant allele detected in the patient. Methods Mutation search for OCA responsible genes was done. A mutant allele with a missense mutation was analyzed using melanocyte cultures (b cells) established from a mouse model of OCA3. Results Compound heterozygous mutations, p.C30R and p.367fsX384, were detected in the Japanese girl. Then we revealed that the missense mutation, p.C30R, was functionally incapable of melanin synthesis with in vitro experiments. Conclusion This is the first report of the occurrence of OCA3 in Japanese population.
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Oculocutaneous Albinism type 4 six novel mutations in the membrane associated transporter protein gene and their phenotypes
Pigment Cell Research, 2006Co-Authors: Katsuhiko Inagaki, Tamio Suzuki, Hiroshi Shimizu, Shiro Ito, Noriyuki Suzuki, Koji Adachi, Torayuki Okuyama, Yusei Nakata, Hironori Matsuura, Takashi OonoAbstract: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.
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Oculocutaneous Albinism type 4 is one of the most common types of Albinism in japan
American Journal of Human Genetics, 2004Co-Authors: Katsuhiko Inagaki, Tamio Suzuki, Kenji Takamori, Hiroshi Shimizu, Norihisa Ishii, Yoshinori Umezawa, Joji Tada, Noriaki Kikuchi, Minoru Takata, Mari KishibeAbstract: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). MATP was recently reported in a single Turkish OCA patient as the fourth pathological gene, but no other patients with OCA4 have been reported. Here, we report the mutational profile of OCA4, determined by genetic analysis of the MATP gene in a large Japanese population with OCA. Of 75 unrelated patients that were screened, 18 individuals (24%) were identified as having OCA4; they harbored seven novel mutations, including four missense mutations (P58S, D157N, G188V, and V507L) and three frameshift mutations (S90CGGCCA→GC, V144insAAGT, and V469delG), showing that MATP is the most frequent locus for tyrosinase-positive OCA in Japanese patients. We discuss the functional melanogenic activity of each mutant allele, judging from the relationship between the phenotypes and genotypes of the patients. This is the first report on a large group of patients with OCA4.
Aihua Wei - One of the best experts on this subject based on the ideXlab platform.
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identification of two chinese Oculocutaneous Albinism type 6 patients and mutation updates of the slc24a5 gene
Journal of Dermatology, 2019Co-Authors: Yunlan Zhang, Xiumin Yang, Yingzi Zhang, Teng Liu, Dayong Bai, Aihua WeiAbstract:Oculocutaneous Albinism (OCA) is a rare and heterogeneous disorder characterized by hypopigmentation of the skin, hair and eyes. Thirty OCA type 6 (OCA6) patients with 24 mutations in SLC24A5 have been reported across various populations; however, only one patient has been identified in a Chinese population. This study identifies two novel SLC24A5 frame-shift variants in two unrelated Chinese patients and both are predicted to be pathogenic by American College of Medical Genetics guidelines. The genotypes and phenotypes of all three Chinese OCA6 patients are unique compared with those identified in other populations. All of the mutations identified to date in Chinese OCA6 patients are predicted to be non-functional, a finding that is useful in guiding genetic diagnosis and counseling for OCA6 in China.
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a comprehensive study of Oculocutaneous Albinism type 1 reveals three previously unidentified alleles on the tyr gene
European Journal of Dermatology, 2014Co-Authors: Yuying Lin, Aihua Wei, Shi Lian, Zhiyong Zhou, Wei ZhuAbstract:Background: Oculocutaneous Albinism (OCA) is a congenital genetic disorder characterized by defects in melanin production. OCA type 1 (OCA1) is the most serious and common type of OCA. This study characterized mutations associated with OCA1 in a series of Chinese patients. Methods: We recruited 41 unrelated patients with OCA and 100 healthy subjects from the Chinese Han population. Genomic DNA was extracted from their blood samples. Mutational analysis of tyrosinase (TYR) genes was conducted using polymerase chain reaction (PCR) and direct sequencing, specifically to test the 100 control subjects and exclude the possibility of polymorphism. Mutational analysis and bioinformatics study were performed in TYR mutations. Results: Among the 24 (58.5%) patients with OCA1, 21 different TYR mutations were identified, including three previously unidentified alleles (PUAs): one frameshift mutation (c.216delA) and two missense mutations (A241T and N364K). The proband mutation A241T carries three possible mutations in complex OCA. Conclusion: The findings of this study expand current knowledge and data of mutations associated with OCA1 in China and allow us to estimate or explore the mutation spectrum and relative frequencies of the TYR gene in the Chinese population.
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exome sequencing identifies slc24a5 as a candidate gene for nonsyndromic Oculocutaneous Albinism
Journal of Investigative Dermatology, 2013Co-Authors: Aihua Wei, Dongjie Zang, Zhe Zhang, Xuanzhu Liu, Lin Yang, Yi Wang, Zhiyong Zhou, Mingrong Zhang, Lanlan DaiAbstract:Oculocutaneous Albinism (OCA) is a heterogeneous and autosomal recessive disorder with hypopigmentation in the eye, hair, and skin color. Four genes, TYR, OCA2, TYRP1, and SLC45A2, have been identified as causative genes for nonsyndromic OCA1-4, respectively. The genetic identity of OCA5 locus on 4q24 is unknown. Additional unknown OCA genes may exist as at least 5% of OCA patients have not been characterized during mutational screening in several populations. We used exome sequencing with a family-based recessive mutation model to determine that SLC24A5 is a previously unreported candidate gene for nonsyndromic OCA, which we designate as OCA6. Two deleterious mutations in this patient, c.591G>A and c.1361insT, were identified. We found apparent increase of immature melanosomes and less mature melanosomes in the patient's skin melanocytes. However, no defects in the platelet dense granules were observed, excluding typical Hermansky-Pudlak syndrome (HPS), a well-known syndromic OCA. Moreover, the SLC24A5 protein was reduced in steady-state levels in mouse HPS mutants with deficiencies in BLOC-1 and BLOC-2. Our results suggest that SLC24A5 is a previously unreported nonsyndromic OCA candidate gene and that the SLC24A5 transporter is transported into mature melanosomes by HPS protein complexes.
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genetic analyses of chinese patients with digenic Oculocutaneous Albinism
Chinese Medical Journal, 2013Co-Authors: Aihua Wei, Xiumin Yang, Shi LianAbstract:Background Oculocutaneous Albinism (OCA) is a heterogeneous and autosomal recessive disorder in all populations worldwide. The mutational spectra of OCA are population-specific. Some OCA patients carry mutations from different OCA genes. In this study, we investigated the frequency of digenic mutations in Chinese OCA patients. Methods Genomic DNAs were extracted from the blood samples of 184 clinically diagnosed OCA patients and 120 unaffected subjects. The amplified DNA segments of the exons and exon-intron boundaries were screened for mutations of TYR, OCA2, TYRP1, SLC45A2, and HPS1 by direct sequencing. To exclude the previously unidentified alleles from polymorphisms, samples from 120 unaffected controls were sequenced for the same regions of variations. Results In all 184 patients, 134 had two pathologic mutations on one locus. Eleven cases had no apparent pathologic mutations in any of the genes studied. Among the remaining 39 patients who had only one pathologic mutation, five patients (2.7% in total) were found to carry the mutational alleles on a second locus in TYR, OCA2 or SLC45A2. Of the five digenic OCA patients, four patients were clinically diagnosed as OCA2 and one patient as OCA1. A previous unidentified allele p.G188D in SLC45A2 was identified, which was not present in the 120 unaffected controls. Conclusions The identification of the digenic OCA patients suggests the synergistic roles among TYR, OCA2 and SLC45A2 during melanin biosynthesis, which may cause OCA under digenic mutations. This information will be useful for gene diagnosis and genetic counseling of OCA in China. Chin Med J 2013;126 (2): 226-230
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Implementation of an optimized strategy for genetic testing of the Chinese patients with Oculocutaneous Albinism.
Journal of dermatological science, 2011Co-Authors: Aihua Wei, Xiumin Yang, Shi LianAbstract:Abstract Background Oculocutaneous Albinism (OCA) is a relatively common inherited disorder in all populations worldwide. The mutational spectra of OCA are population-specific. Objective Based on our previous molecular epidemiological studies, we have implemented an optimized strategy for the genetic testing of Chinese OCA patients. Methods Genomic DNA was extracted from the blood samples of 52 clinically diagnosed OCA patients and 100 unaffected subjects. The amplified DNA segments were screened for mutations of TYR, OCA2, TYRP1, SLC45A2 and HPS1 by direct sequencing. To exclude the previously unidentified alleles (PUAs) from polymorphisms, samples from 100 unaffected controls were sequenced for the same regions of variations. Results Among the 52 OCA patients, 26 (50.0%) were found mutations on TYR gene, 8 (15.4%) on OCA2, 12 (23.1%) on SLC45A2, 2 (3.8%) on HPS1, and 4 (7.7%) patients uncharacterized. We identified 18 PUAs in these patients, 2 in TYR, 7 in OCA2, 8 in SLC45A2, and 1 in HPS1. Conclusion The optimized method to screen the OCA mutations is efficiently implemented in the routine genetic testing of Chinese OCA patients accompanied with genetic counseling.
Hiroshi Shimizu - One of the best experts on this subject based on the ideXlab platform.
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Oculocutaneous Albinism type 4 six novel mutations in the membrane associated transporter protein gene and their phenotypes
Pigment Cell Research, 2006Co-Authors: Katsuhiko Inagaki, Tamio Suzuki, Hiroshi Shimizu, Shiro Ito, Noriyuki Suzuki, Koji Adachi, Torayuki Okuyama, Yusei Nakata, Hironori Matsuura, Takashi OonoAbstract: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.
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tyrosinase gene analysis in japanese patients with Oculocutaneous Albinism
Journal of Dermatological Science, 2004Co-Authors: Maki Goto, Kazuko C Satomatsumura, Daisuke Sawamura, Koichi Yokota, Hideki Nakamura, Hiroshi ShimizuAbstract:Summary Background: Oculocutaneous Albinism (OCA) is a heterogeneous congenital disorder. Tyrosinase is a key enzyme in melanin biosynthesis, and tyrosinase gene mutations cause the OCA1 subtype. Objective: This study was intended evaluate the frequency and details of tyrosinase gene mutations in Japanese OCA patients. Patients and methods: We examined nine non-consanguineous OCA families, sequenced the tyrosinase gene of the patients and also confirmed a splicing site mutation using exon trapping system. Results: Tyrosinase gene mutations were identified in five out of nine OCA families (55%). IVS2-10deltt-7t-a was present in 3 out of 18 alleles in three families (16%), P310insC was present in three alleles in three families (16%) and R278X was found in three alleles (16%), including those in one heterozygous and one compound homozygous patient. G97V (290 G-T) was found in 1 out of 18 alleles, and we could not find G97V in the mutation database. We have added this mutation as 9th mutation of Japanese OCA1 patients. In 8 of 18 alleles, four families, no tyrosinase mutations were identified. They were presumed not to be OCA1, but other subtypes of OCA. Exon trapping system demonstrated IVS2-10deltt-7t-a mutation generated the abnormal splicing site, and inserted the codon 4 bases in mRNA level resulting in premature termination codon downstream. Conclusion: This study provided new information about OCA1 mutations, and highlights the requirement of broader detailed search to make precise diagnosis of OCA.
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Oculocutaneous Albinism type 4 is one of the most common types of Albinism in japan
American Journal of Human Genetics, 2004Co-Authors: Katsuhiko Inagaki, Tamio Suzuki, Kenji Takamori, Hiroshi Shimizu, Norihisa Ishii, Yoshinori Umezawa, Joji Tada, Noriaki Kikuchi, Minoru Takata, Mari KishibeAbstract: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). MATP was recently reported in a single Turkish OCA patient as the fourth pathological gene, but no other patients with OCA4 have been reported. Here, we report the mutational profile of OCA4, determined by genetic analysis of the MATP gene in a large Japanese population with OCA. Of 75 unrelated patients that were screened, 18 individuals (24%) were identified as having OCA4; they harbored seven novel mutations, including four missense mutations (P58S, D157N, G188V, and V507L) and three frameshift mutations (S90CGGCCA→GC, V144insAAGT, and V469delG), showing that MATP is the most frequent locus for tyrosinase-positive OCA in Japanese patients. We discuss the functional melanogenic activity of each mutant allele, judging from the relationship between the phenotypes and genotypes of the patients. This is the first report on a large group of patients with OCA4.
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a novel p gene missense mutation in a japanese patient with Oculocutaneous Albinism type ii oca2
Journal of Dermatological Science, 2003Co-Authors: Atsushi Kato, Kazuyoshi Fukai, Hiroshi Shimizu, Naoki Oiso, Naoko Hosomi, Shinji Saitoh, Takahito Wada, Masamitsu IshiiAbstract: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. Mutaions 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.
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six novel p gene mutations and Oculocutaneous Albinism type 2 frequency in japanese albino patients
Journal of Investigative Dermatology, 2003Co-Authors: Tamio Suzuki, Hiroshi Shimizu, Yoshinori Miyamura, Jun Matsunaga, Yasuhiro Kawachi, Naoko Ohyama, Osamu Ishikawa, Tomoyuki Ishikawa, Hiroshi Terao, Yasushi TomitaAbstract:Type 2 Oculocutaneous Albinism (OCA2) is an autosomal recessive disorder that results from mutations in the P gene that codes one of the melanosomal proteins, the function of which remains unknown. In this paper, we report the frequency of OCA2, 8%, among the Japanese albino population, six novel mutations containing four missense substitutions (P198L, P211L, R10W, M398I), and two splice site mutations (IVS15+1 G>A, IVS24-1 G>C). One of them, R10W, was within the putative signal peptide at the N-terminal of the P protein. This is the first report on the frequency of OCA2 in the Japanese albino population.
