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Richard A Spritz - One of the best experts on this subject based on the ideXlab platform.
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comprehensive analysis of oculocutaneous albinism among non hispanic caucasians shows that oca1 is the most prevalent oca type
Journal of Investigative Dermatology, 2008Co-Authors: Saunie M Hutton, Richard A SpritzAbstract:Oculocutaneous albinism (OCA) is a genetically heterogeneous group of disorders characterized by absent or reduced pigmentation of the skin, hair, and eyes. In humans, four genes have been associated with "classical" OCA and another 12 genes with syndromic forms of OCA. To assess the prevalence of different forms of OCA and different gene mutations among non-Hispanic Caucasian patients, we performed DNA sequence analysis of the four genes associated with "classical" OCA (TYR, OCA2, TYRP1, SLC45A2), the two principal genes associated with syndromic OCA (HPS1, HPS4), and a candidate OCA gene (SILV), in 121 unrelated, unselected non-Hispanic/Latino Caucasian patients carrying the clinical diagnosis of OCA. We identified apparent pathologic TYR gene mutations in 69% of patients, OCA2 mutations in 18%, SLC45A2 mutations in 6%, and no apparent pathological mutations in 7% of patients. We found no mutations of TYRP1, HPS1, HPS4, or SILV in any patients. Although we observed a diversity of mutations for each gene, a relatively small number of different mutant alleles account for a majority of the total. This study demonstrates that, contrary to long-held clinical lore, OCA1, not OCA2, is by far the most frequent cause of OCA among Caucasian patients.
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a comprehensive genetic study of autosomal recessive ocular albinism in caucasian patients
Investigative Ophthalmology & Visual Science, 2008Co-Authors: Saunie M Hutton, Richard A SpritzAbstract:PURPOSE. Autosomal recessive ocular albinism (AROA) is a group of genetic disorders in which reduced pigmentation of the eye is associated with decreased visual acuity, nystagmus, strabismus, and photophobia, although pigmentation of skin and hair is relatively normal. Previous studies have shown that AROA in some cases constitutes a clinically mild presentation of oculocutaneous albinism (OCA), due to mutations in either the TYR (OCA1) or OCA2 (P) genes. The purpose of this study was to characterize the relative prevalence of different genetic forms of AROA, and to characterize a sample repertoire of gene mutations in a large series of Caucasian patients with AROA. METHODS. Thirty-six unrelated Caucasian patients carrying the clinical diagnosis of AROA were studied by DNA sequence analysis of the four classic OCA genes: TYR, OCA2 (F), TYRP1, and SLC45A2 (MATP), as appropriate. In all patients with no apparent pathologic mutations in these genes, DNA sequence analysis was performed of a candidate OCA gene, SILV, and the two genes most often involved in Hermansky-Pudlak syndrome, HPS1 and HPS4, the most frequent syndromic form of OCA. RESULTS. TYR gene mutations were identified in 20 (56%) patients, OCA2 mutations in 3 (8%), mutations in both TYR and OCA2 in 2 (6%), and possible TYRP1 mutations in 2 (6%). In at least nine patients, no mutations were found in any of the genes studied. Almost all patients with OCA1-related AROA were compound heterozygous for severe OCA1 mutant alleles and the common R402Q variant. CONCLUSIONS. Most patients with AROA represent phenotypically mild variants of OCA, well over half of which is OCA1.
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complementation of hypopigmentation in p mutant pink eyed dilution mouse melanocytes by normal human p cdna and defective complementation by OCA2 mutant sequences
Journal of Investigative Dermatology, 1997Co-Authors: Elena V Sviderskaya, Dorothy C Bennett, Seung Taek Lee, Tu Bailin, Richard A SpritzAbstract:Mutations in the P gene of humans and the homologous p-locus of mice, respectively, result in the homologous disorders oculocutaneous albinism type 2 (OCA2) and pink-eyed dilution. Although clearly required for melanin biosynthesis, the specific function of the P gene product, a melanosomal transmembrane protein expressed in melanocytes of the skin, hair and eyes, is not yet known. Here we describe lines of immortal melanocytes and melanoblasts from mice of the null genotype pcpp25H. These p-null melanocytes were severely hypopigmented, although they and the melanoblasts expressed mRNAs for a number of melanosomal proteins. Proliferation of the p-null melanoblasts was normal. Both diploid and immortal p-null melanocytes grew more slowly than wild-type melanocytes, however and were unusually susceptible to the antibiotic G418; these abnormalities were corrected by culture in high concentrations of L-tyrosine. Transfection of the p-null melanocytes with full-length normal human P cDNA resulted in complementation of deficient melanin biosynthesis and hypopigmentation. In contrast, transfection mutant human P cDNAs containing amino acid substitutions (A481T, V443I) found in patients with OCA2 resulted in minimal or partial correction, consistent with the corresponding pigmentation phenotypes in patients with these mutations. These results demonstrate the utility of this model system for distinguishing true OCA2 mutations from nonpathologic polymorphisms and for quantitating the effect of these mutations on P function.
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frequent intragenic deletion of the p gene in tanzanian patients with type ii oculocutaneous albinism OCA2
American Journal of Human Genetics, 1995Co-Authors: Richard A Spritz, Kazuyoshi Fukai, Stuart A Holmes, J LuandeAbstract:Type II oculocutaneous albinism (OCA2) is an autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in the skin, hair, and eyes. OCA2, which results from mutations of the P gene, is the most frequent type of albinism in African and African-American patients. OCA2 is especially frequent in Tanzania, where it occurs with an incidence of approximately 1/1,400. We have identified abnormalities of the P gene in each of 13 unrelated patients with OCA2 from Tanzania. One of these, a deletion of exon 7, is strongly predominant, accounting for approximately 77% of mutant alleles in this group of patients.
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diverse mutations of the p gene among african americans with type ii tyrosinase positive oculocutaneous albinism OCA2
Human Molecular Genetics, 1994Co-Authors: Seung Taek Lee, Robert D Nicholls, Rhonda E Schnur, Leticia C Guida, Jennifer Lukuo, Nancy B Spinner, Elaine H Zackai, Richard A SpritzAbstract:Type II (tyrosinase-positive) oculocutaneous albinism (OCA2) is an autosomal recessive disorder in which the biosynthesis of melanin pigment is reduced in the skin, hair, and eyes. OCA2, which we have shown results from mutations of the P gene in Caucasians, is the most prevalent type of oculocutaneous albinism in African and African-American patients with OCA. We have identified abnormalities of the P gene in seven unrelated African-American patients with OCA2, including three large deletions, two small in-frame deletions, and six different point mutations. None of these appears to be predominant among African-American patients with OCA2.
Richard A King - 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, Jacy Pietsch, James P Fryer, 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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mutations in the human orthologue of the mouse underwhite gene uw underlie a new form of oculocutaneous albinism oca4
American Journal of Human Genetics, 2001Co-Authors: J M Newton, Richard A King, Orit Cohenbarak, Nobuko Hagiwara, John M Gardner, Muriel T Davisson, Murray H BrilliantAbstract:Oculocutaneous albinism (OCA) affects ∼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 ∼40% of OCA worldwide. OCA2 (MIM 203200), the most common form of OCA, is associated with mutations of the P gene and accounts for ∼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.
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Molecular basis of albinism: Mutations and polymorphisms of pigmentation genes associated with albinism
Human Mutation, 1999Co-Authors: William S. Oetting, Richard A KingAbstract:Albinism, caused by a deficiency of melanin pigment in the skin, hair, and eye (oculocutaneous albinism [OCA]), or primarily in the eye (ocular albinism [OA]), results from mutations in genes involved in the biosynthesis of melanin pigment. The lack of melanin pigment in the developing eye leads to fovea hypoplasia and abnormal routing of the optic nerves. These changes are responsible for the nystagmus, strabismus, and reduced visual acuity common to all types of albinism. Mutations in six genes have been reported to be responsible for different types of oculocutaneous and ocular albinism, including the tyrosinase gene (TYR) and OCA1 (MIM# 203100), the OCA2 gene and OCA2 (MIM# 203200), the tyrosinase-related protein-1 gene (TYRP1) and OCA3 (MIM# 203290), the HPS gene and Hermansky-Pudlak syndrome (MIM# 203300), the CHS gene (CHS1), and Chediak-Higashi syndrome (MIM# 214500), and the X-linked ocular albinism gene and OA1 (MIM#300500). The function of only two of the gene products is known tyrosinase and tyrosinase-related protein-1 both of which are enzymes in the melanin biosynthetic pathway. Continued mutational analysis coupled with function/structure studies should aid our understanding of the function of the remaining genes and their role in albinism. Mutation and polymorphism data on these genes are available from the International Albinism Center Albinism Database web site (http://www.cbc.umn.edu/tad). Hum Mutat 13:99–115, 1999. © 1999 Wiley-Liss, Inc.
Horst Wilkens - One of the best experts on this subject based on the ideXlab platform.
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albinism in phylogenetically and geographically distinct populations of astyanax cavefish arises through the same loss of function OCA2 allele
Heredity, 2013Co-Authors: Joshua B Gross, Horst WilkensAbstract:Albinism in phylogenetically and geographically distinct populations of Astyanax cavefish arises through the same loss-of-function OCA2 allele
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albinism in phylogenetically and geographically distinct populations of astyanax cavefish arises through the same loss of function OCA2 allele
Heredity, 2013Co-Authors: Joshua B Gross, Horst WilkensAbstract:The Mexican tetra, Astyanax mexicanus, comprises 29 populations of cave-adapted fish distributed across a vast karst region in northeastern Mexico. These populations have a complex evolutionary history, having descended from 'old' and 'young' ancestral surface-dwelling stocks that invaded the region ∼6.7 and ∼2.8 MYa, respectively. This study investigates a set of captive, pigmented Astyanax cavefish collected from the Micos cave locality in 1970, in which albinism appeared over the past two decades. We combined novel coloration analyses, coding sequence comparisons and mRNA expression level studies to investigate the origin of albinism in captive-bred Micos cavefish. We discovered that albino Micos cavefish harbor two copies of a loss-of-function ocular and cutaneous albinism type II (OCA2) allele previously identified in the geographically distant Pachon cave population. This result suggests that phylogenetically young Micos cavefish and phylogenetically old Pachon cave fish inherited this OCA2 allele from the ancestral surface-dwelling taxon. This likely resulted from the presence of the loss-of-function OCA2 haplotype in the 'young' ancestral surface-dwelling stock that colonized the Micos cave and also introgressed into the ancient Pachon cave population. The appearance of albinism in captive Micos cavefish, caused by the same loss-of-function allele present in Pachon cavefish, implies that geographically and phylogenetically distinct cave populations can evolve the same troglomorphic phenotype from standing genetic variation present in the ancestral taxon.
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genetic analysis of cavefish reveals molecular convergence in the evolution of albinism
Nature Genetics, 2006Co-Authors: Meredith E Protas, Horst Wilkens, Candace Hersey, Dawn Kochanek, Yi Zhou, William R Jeffery, Leonard I Zon, Richard Borowsky, Clifford J TabinAbstract:The genetic basis of vertebrate morphological evolution has traditionally been very difficult to examine in naturally occurring populations. Here we describe the generation of a genome-wide linkage map to allow quantitative trait analysis of evolutionarily derived morphologies in the Mexican cave tetra, a species that has, in a series of independent caves, repeatedly evolved specialized characteristics adapted to a unique and well-studied ecological environment. We focused on the trait of albinism and discovered that it is linked to OCA2, a known pigmentation gene, in two cave populations. We found different deletions in OCA2 in each population and, using a cell-based assay, showed that both cause loss of function of the corresponding protein, OCA2. Thus, the two cave populations evolved albinism independently, through similar mutational events.
Axel Meyer - One of the best experts on this subject based on the ideXlab platform.
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genome of the malawi golden cichlid fish melanochromis auratus reveals exon loss of OCA2 in an amelanistic morph
Pigment Cell & Melanoma Research, 2019Co-Authors: Claudius F Kratochwil, Sabine Urban, Axel MeyerAbstract:The tropical freshwater fish family Cichlidae is famous for its record-breaking rates of speciation and diversity in colors and color patterns. Here, we sequenced the genome of the Lake Malawi cichlid Melanochromis auratus to study the genetic basis of an amelanistic morph of this species that lacks the typical melanic stripes and markings. Genome sequencing of the amelanistic and wild-type morph revealed the loss of the second exon of the known pigmentation gene oculocutaneous albinism II (OCA2), also known as p(ink-eyed dilution) gene or melanocyte-specific transporter gene. Additional genotyping confirms the complete association with this recessive Mendelian phenotype. The deletion results in a shorter transcript, lacking an acidic di-leucine domain that is crucial for trafficking of the OCA2 protein to melanosomes. The fact that OCA2 is involved in a wide range of amelanistic morphs across vertebrates demonstrates its highly conserved function.
Murray H Brilliant - One of the best experts on this subject based on the ideXlab platform.
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albinism in africa a medical and social emergency
International Health, 2015Co-Authors: Murray H BrilliantAbstract:People with albinism (PWA) face a variety of medical and social problems, ranging from poor vision and skin cancer to murder for their body parts for witchcraft in East Africa, notably Tanzania. Albinism is an inherited disorder of melanin biosynthesis that results in a variable phenotype classified according to the mutation in one of several genes. All forms of albinism are associated with problems of the visual system resulting in abnormalities of the retina, nystagmus, strabismus, foveal hypoplasia, abnormal crossing of the optic fibers, photophobia and reduced visual acuity. Oculocutaneous albinism (OCA) is a subgroup of recessive forms of albinism and characterized by a significant reduction or absence of melanin pigment in the eyes, skin and hair. Several genes are associated with OCA, although the most common forms are OCA1 and OCA2. OCA1 is caused by a reduction or complete lack of activity of the tyrosinase enzyme encoded by the TYR gene. OCA2 is caused by a reduction or complete lack of activity of the P protein—a chloride channel that helps regulate the pH of the melanosome organelle where tyrosinase is active. Although OCA2 is found in all populations, certain populations have a relatively high incidence. The worldwide incidence of OCA2 is 1 in 36 000, but it is especially common among individuals of African descent. The phenotype of sandy colored hair, chalky white skin and blue or hazel eyes is very distinctive in African populations (Figure 1). High OCA2 frequencies are seen among various African tribes: 1 in 1100 among the Ibo of Nigeria, 1 in 7900 among the Bamileke of Cameroon, 1 in 3900 in South Africa and 1 in 1400 in Tanzania. Therefore, Tanzania has one of theworld’s highest rates of albinism. The most common form of mutation among the OCA2 PWAs in Tanzania is a specific deletion of exon 7 of the OCA2 gene accounting for 77% of the mutant alleles. This same mutation is commonly found among other Africans and African-Americans and appears to be derived from a common African ancestor who lived 2000–5000 years ago. In addition to their vision problems, PWAs are also highly susceptible to skin cancer with high rates of squamous and basal cell carcinoma.Sunscreens are expensive and often unavailable in many parts of Africa, so health intervention strategies mainly focus on encouraging sun avoidance and protection from an early age. Historically, some tribes have killed newborns with albinism and those that survive are often discriminated against as marriage partners. Since people with albinism have fewer children, as a result of murders and social customs, there must be a reason that heterozygous frequency for OCA2 is so prevalent, especially in Tanzania. One possible insight derives from the observation that the OCA2 protein shares amino acid homology with 38L, a protein of unknown function in the Mycobacteria, such as Mycobacterium leprae, the bacteria that causes leprosy or Hansen’s disease. Moreover, among the first signs of leprosy are hypopigmented patches, suggesting that pigment cells may play a role in the etiology of the disease. Leprosy has been historically high and endemic in Tanzania, where OCA2 and carriers for OCA2 are also very high. Thus, there is circumstantial evidence for a relationship between the high prevalence of OCA2 and leprosy. Sadly, in the past few years, PWAs in Tanzania face an additional threat. They are being murdered at an alarming rate for their body parts (primarily bones and hair) used for witchcraft purposes. Local superstition holds that the bones, hair and other body parts of a PWA can be used in potions believed to be magical for success in finding things, such as in mining. In the past, obtaining of body parts was largely limited to grave robbing, but living people are increasingly targeted now for murder and mutilation for their body parts. In particular, the bones of a PWA are quite valuable for these witchcraft uses, with the highest price paid for the bones of children (Figure 2). While it is proper to respect rituals, beliefs and traditions that are not our own, the murder and maiming of innocent people can never be justified. Recently, under increased international pressure, the Tanzanian government has outlawed these practices by witch doctors, yet the murders and mutilations continue. Because of the high rate of OCA2 in Tanzania, 1 in 19 people are carriers for the ancestral mutation. Ironically, it is highly likely that this mutation is also carried by at least a few of the murderers of PWA. Perhaps if the people of Tanzania knew that PWAs are a manifestation of one of their ancestors, the murders would stop.
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albinism and disease causing pathogens in tanzania are alleles that are associated with OCA2 being maintained by balancing selection
Medical Hypotheses, 2012Co-Authors: Murray H Brilliant, Abbas M Tuli, Robert K Valenzuela, Erasmus KamugishaAbstract:Abstract Oculocutaneous albinism type 2 (OCA2) is present at significantly higher frequencies in sub-Saharan African populations compared to populations in other regions of the world. In Tanzania and other sub-Saharan countries, most OCA2 is associated with a common 2.7kb deletion allele. Leprosy is also in high prevalence in sub-Saharan African populations. The infectious agent of leprosy, Mycobacterium leprae , contains a gene, 38L, that is similar to OCA2. Hypopigmented patches of skin are early symptoms that present with infection of leprosy. In consideration of both the genetic similarity of OCA2 and the 38L gene of M. leprae and the involvement of pigmentation in both disorders, we hypothesized that the high rates of OCA2 may be due to heterozygote advantage. Hence, we hypothesized that carriers of the 2.7kb deletion allele of OCA2 may provide a protective advantage from infection with leprosy. We tested this hypothesis by determining the carrier frequency of the 2.7kb deletion allele from a sample of 240 individuals with leprosy from Tanzania. The results were inconclusive due to the small sample size; however, they enabled us to rule out a large protective effect, but perhaps not a small advantage. Mycobacterium tuberculosis is another infectious organism prevalent in sub-Saharan Africa that contains a gene, arsenic-transport integral membrane protein that is also similar to OCA2. Interestingly, chromosomal region 15q11-13, which also contains OCA2, was reported to be linked to tuberculosis susceptibility. Although variants within OCA2 were tested for association, the 2.7kb deletion allele of OCA2 was not tested. This led us to hypothesize that the deletion allele may confer resistance to susceptibility. Confirmation of our hypothesis would enable development of novel pharmocogenetic therapies for the treatment of tuberculosis, which in turn, may enable development of drugs that target other pathogens that utilize a similar infection mechanism as M. tuberculosis . From an evolutionary perspective, confirmation of our hypothesis may provide another example of heterozygote advantage.
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mutations in the human orthologue of the mouse underwhite gene uw underlie a new form of oculocutaneous albinism oca4
American Journal of Human Genetics, 2001Co-Authors: J M Newton, Richard A King, Orit Cohenbarak, Nobuko Hagiwara, John M Gardner, Muriel T Davisson, Murray H BrilliantAbstract:Oculocutaneous albinism (OCA) affects ∼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 ∼40% of OCA worldwide. OCA2 (MIM 203200), the most common form of OCA, is associated with mutations of the P gene and accounts for ∼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.
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mutations of the human p gene associated with type ii oculocutaneous albinism OCA2 mutations in brief no 205 online
Human Mutation, 1998Co-Authors: William S. Oetting, Richard A King, John M Gardner, James P Fryer, A Ching, D Durhampierre, Murray H BrilliantAbstract:Mutations in the human P gene lead to oculocutaneous albinism type 2 (OCA2, MIM #203200), the most common type of albinism in humans. The P gene encodes a 110 kDa protein that is associated with melonosomal membranes and contains 12 potential membrane spanning domains. The specific function of the P protein is currently unknown. We report 7 new mutations in the P gene associated with OCA2. This includes 6 missense mutations (S86R, C112F, A368V, T592I, A724P and A787V) and one frameshift mutation (1047del7). We also report 8 polymorphisms including one amino acid substitution, D/A257. We and others have found many polymorphisms of the P gene in the coding region, several of which result in amino acid substitutions, making molecular diagnosis problematic. In contrast to this is the tyrosinase gene associated with OCA1, with a limited number of polymorphic variations in the coding region. There is also no apparent clustering of P gene missense mutations in contrast to the clustering observed by the tyrosinase gene missense mutations that define functional domains of the protein. Further mutational analysis is needed to help define the critical functional domains of the P protein and to allow a definitive diagnosis of OCA2.
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mutations of the human p gene associated with type ii oculocutaneous albinism OCA2
Human Mutation, 1998Co-Authors: William S. Oetting, Richard A King, John M Gardner, James P Fryer, A Ching, D Durhampierre, Murray H BrilliantAbstract:Mutations in the human P gene lead to oculocutaneous albinism type 2 (OCA2, MIM #203200), the most common type of albinism in humans. The P gene encodes a 110 kDa protein that is associated with melanosomal membranes and contains 12 potential membrane spanning domains. The specific function of the P protein is currently unknown. We report 7 new mutations in the P gene associated with OCA2. This includes 6 missense mutations (S86R, C112F, A368V, T592I, A724P and A787V) and one frameshift mutation (1047del7). We also report 8 polymorphisms including one amino acid substitution, D/A257. We and others have found many polymorphisms of the P gene in the coding region, several of which result in amino acid substitutions, making molecular diagnosis problematic. In contrast to this is the tyrosinase gene associated with OCA1, with a limited number of polymorphic variations in the coding region. There is also no apparent clustering of P gene missense mutations in contrast to the clustering observed by the tyrosinase gene missense mutations that define functional domains of the protein. Further mutational analysis is needed to help define the critical functional domains of the P protein and to allow a definitive diagnosis of OCA2. © 1998 Wiley-Liss, Inc.
