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: 5.14). 03/2004; 23(2):106-10. DOI: 10.1002/humu.10311
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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 In this first report on West European patients, we describe 10 so far unpublished mutations, as well as two intronic variations, in addition to two known polymorphisms.

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    • "The function of SLC45A2 is still unknown, but studies from Medaka fish show that the SLC45A2 protein plays an important role in pigmentation and probably functions as a membrane transporter in melanosomes [53]. Mutations in SLC45A2 were found for the first time in a Turkish OCA patient [52] and have since been found in German, Japanese, and Korean OCA patients [20, 55–57]. Mutations in SLC45A2 cause misrouting of tyrosinase similar to the cellular phenotype of OCA-2 [58, 59]. "
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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(1):905472. DOI:10.1155/2014/905472 · 1.58 Impact Factor
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    • "The prevalence of all known forms of albinism in the best-studied Western populations, mostly in North America and Europe, appears to be 1:17 000 newborns (within a range of 1:10 000–20 000) (Gargiulo et al., 2011; Grønskov et al., 2007, 2009; Hutton and Spritz, 2008a,b; King and Oetting, 2006; Oetting and King, 1999; Rooryck et al., 2008; Rundshagen et al., 2004; Z€ uhlke et al., 2007). Different frequencies of several types of albinism have been also reported from Asia (Inagaki et al., 2004; Lin et al., 2006; Suzuki and Tomita, 2008; Wei and Li, 2013; Wei et al., 2010, 2011), whereas the highest prevalence is found in some countries in Africa, mostly due to consanguinity issues and founder effects (Aquaron et al., 2007; Cruz-Inigo et al., 2011; Spritz et al., 1995) (Figure 1). "
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    ABSTRACT: Albinism is a rare genetic condition globally characterized by a number of specific deficits in the visual system, resulting in poor vision, in association with a variable hypopigmentation phenotype. This lack or reduction of pigment might affect the eyes, skin and hair (oculocutaneous albinism, OCA), or only the eyes (ocular albinism, OA). In addition, there are several syndromic forms of albinism (e.g., Hermansky-Pudlak and Chediak-Higashi syndromes, HPS and CHS, respectively) in which the described hypopigmented and visual phenotypes coexist with more severe pathological alterations. Recently, a locus has been mapped to the 4q24 human chromosomal region and thus represents an additional genetic cause of OCA, termed OCA5, while the gene is eventually identified. In addition, two new genes have been identified as causing OCA when mutated: SLC24A5 and C10orf11, and hence designated as OCA6 and OCA7, respectively. This consensus review, involving all laboratories that have reported these new genes, aims to update and agree upon the current gene nomenclature and types of albinism, while providing additional insights from the function of these new genes in pigment cells. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 09/2013; 27(1). DOI:10.1111/pcmr.12167 · 4.62 Impact Factor
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    • "Our exome data showed the same OCA4 mutation [c.986delC, p.T329RfsX68], which we confirmed by Sanger sequencing as homozygous in the proband and heterozygous in her brother. The c.986delC variant was previously reported as a mutation in five German OCA4 patients [14]. "
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    ABSTRACT: Background Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3). Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4) is caused by autosomal recessive mutations in SLC45A2. Methods We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature. Results The siblings’ phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with “partial OCA” in childhood. Conclusions This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.
    BMC Medical Genetics 11/2012; 13(1):111. DOI:10.1186/1471-2350-13-111 · 2.08 Impact Factor
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