Mutations in the MATP gene in five German patients affected by oculocutaneous albinism type 4.

Institut für Humangenetik der Universität Lübeck, Lübeck, Germany.
Human Mutation (Impact Factor: 5.05). 03/2004; 23(2):106-10. DOI: 10.1002/humu.10311
Source: PubMed

ABSTRACT Oculocutaneous albinism (OCA) is caused by a deficiency of melanin synthesis and characterized by generalized hypopigmentation of skin, hair, and eyes. Due to the hypopigmentation of the retinal pigment epithelium, OCA is usually associated with congenital visual impairment, in addition to an increased risk of skin cancer. OCA is a genetically heterogeneous disease with distinct types resulting from mutations in different genes involved in the pathway which results in pigmentation. OCA1 is associated with mutations in the TYR gene encoding tyrosinase. OCA2 results from mutations in the P gene encoding the P protein and is the most common form of OCA. OCA3, also known as rufous/red albinism, is caused by mutations in the TYRP1 gene, which encodes the tyrosinase-related protein 1. Recently, OCA4 was described as a new form of OCA in a single patient with a splice site mutation in the MATP gene (or AIM1), the human ortholog of the murine underwhite gene. The similarity of MATP to transporter proteins suggests its involvement in transport functions, although its actual substrate is still unclear. We screened 176 German patients with albinism for mutations within the MATP gene and identified five individuals with OCA4. In this first report on West European patients, we describe 10 so far unpublished mutations, as well as two intronic variations, in addition to two known polymorphisms.

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    ABSTRACT: Gunnarsson, U. 2009. Genetic Studies of Pigmentation in Chicken. Acta Universitatis Upsaliensis. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 428. 44 pp. Uppsala. 978-91-554-7439-3. Domestic animals have been selected by humans for thousands of years, which have drastically altered their genetic constitution and phenotypes. In this thesis, several of the most important genes causing pigmentation differences between the wild red junglefowl (Gallus gallus) and domestic chickens have been identified. Pigmentation phenotypes are easily scored, and the genes underlying these phenotypes are valuable models to study gene function and gene interaction. Dominant white colour is widespread among domestic chickens. The Dominant white allele specifically inhibits the expression of black (eumelanin) pigment and we identified several insertion/deletion mutations in the PMEL17 gene causing the different phenotypes controlled by this locus. The Silver allele on the other hand inhibits the expression of red (pheomelanin) colour and is a genetic variant of the SLC45A2 gene. Silver is the first pheomelanin-specific mutation(s) reported for this gene. An 8 kb deletion, including a conserved enhancer element, 14 kb upstream of the transcription factor SOX10 is causing the Dark brown phenotype. This phenotype restricts the expression of eumelanin and enhances red pheomelanin in specific parts of the plumage. These three gene identifications have extended the knowledge about genes affecting melanocyte function. Carotenoid-based pigmentation is of utmost importance in birds and other animals. The yellow skin allele in chicken allows deposition of carotenoids in skin and explains why most domestic chickens have yellow legs. We demonstrated that the yellow skin phenotype is caused by a tissue specific regulatory mutation in the gene for the enzyme beta-caroten dioxygenase 2 (BCDO2). This was the first identification of a specific gene underlying carotenoid-based pigmentation. Interestingly, the yellow skin haplotype was shown to originate from the grey junglefowl (Gallus sonneratii) and not the red junglefowl as expected, thus presenting the first conclusive evidence for a hybrid origin of the domestic chicken.
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    ABSTRACT: The first white Doberman pinscher (WDP) dog was registered by the American Kennel Club in 1976. The novelty of the white coat color resulted in extensive line breeding of this dog and her offspring. The WDP phenotype closely resembles human oculocutaneous albinism (OCA) and clinicians noticed a seemingly high prevalence of pigmented masses on these dogs. This study had three specific aims: (1) produce a detailed description of the ocular phenotype of WDPs, (2) objectively determine if an increased prevalence of ocular and cutaneous melanocytic tumors was present in WDPs, and (3) determine if a genetic mutation in any of the genes known to cause human OCA is causal for the WDP phenotype. WDPs have a consistent ocular phenotype of photophobia, hypopigmented adnexal structures, blue irides with a tan periphery and hypopigmented retinal pigment epithelium and choroid. WDPs have a higher prevalence of cutaneous melanocytic neoplasms compared with control standard color Doberman pinschers (SDPs); cutaneous tumors were noted in 12/20 WDP (<5 years of age: 4/12; >5 years of age: 8/8) and 1/20 SDPs (p<0.00001). Using exclusion analysis, four OCA causative genes were investigated for their association with WDP phenotype; TYR, OCA2, TYRP1 and SLC45A2. SLC45A2 was found to be linked to the phenotype and gene sequencing revealed a 4,081 base pair deletion resulting in loss of the terminus of exon seven of SLC45A2 (chr4∶77,062,968-77,067,051). This mutation is highly likely to be the cause of the WDP phenotype and is supported by a lack of detectable SLC45A2 transcript levels by reverse transcriptase PCR. The WDP provides a valuable model for studying OCA4 visual disturbances and melanocytic neoplasms in a large animal model.
    PLoS ONE 03/2014; 9(3):e92127. DOI:10.1371/journal.pone.0092127 · 3.53 Impact Factor
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    ABSTRACT: Oculocutaneous albinism (OCA) is an autosomal recessive disorder caused by either complete lack of or a reduction of melanin biosynthesis in the melanocytes. The OCA1A is the most severe type with a complete lack of melanin production throughout life, while the milder forms OCA1B, OCA2, OCA3, and OCA4 show some pigment accumulation over time. Mutations in TYR, OCA2, TYRP1, and SLC45A2 are mainly responsible for causing oculocutaneous albinism. Recently, two new genes SLC24A5 and C10orf11 are identified that are responsible to cause OCA6 and OCA7, respectively. Also a locus has been mapped to the human chromosome 4q24 region which is responsible for genetic cause of OCA5. In this paper, we summarized the clinical and molecular features of OCA genes. Further, we reviewed the screening of pathological mutations of OCA genes and its molecular mechanism of the protein upon mutation by in silico approach. We also reviewed TYR (T373K, N371Y, M370T, and P313R), OCA2 (R305W), TYRP1 (R326H and R356Q) mutations and their structural consequences at molecular level. It is observed that the pathological genetic mutations and their structural and functional significance of OCA genes will aid in development of personalized medicine for albinism patients.
    BioMed Research International 06/2014; 2014:905472. DOI:10.1155/2014/905472 · 2.71 Impact Factor

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