A missense mutation in PMEL17 is associated with the Silver coat color in the horse

Brunberg, Emma; Andersson, Leif; Cothran, Gus; Sandberg, K.; Mikko, Sofia; Lindgren, Gabriella

doi:10.1186/1471-2156-7-46

Cited by 140 publications

(74 citation statements)

References 29 publications

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“…The function of the Pmel17 fibrils is not entirely clear, but several studies suggest that they play a cytoprotective role by sequestering toxic intermediates produced during melanin synthesis and/or by templating and accelerating melanin production (3,4). Consistent with this notion, mutations in Pmel17 result in pigment dilution in a number of animal models, at least some of which are associated with poor health or viability of melanocytes (5)(6)(7)(8)(9)(10)(11). Moreover, Pmel17 fibrils from purified melanosomes bind amyloidogenic dyes such as Congo red and thioflavin S, and fibrils formed from purified recombinant Pmel17 isoforms resemble cross-␤-sheet amyloid fibrils by a number of criteria (e.g.…”

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confidence: 62%

N-terminal Domains Elicit Formation of Functional Pmel17 Amyloid Fibrils

Watt

Niel

Fowler

et al. 2009

Journal of Biological Chemistry

102

154

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Pmel17 is a transmembrane protein that mediates the early steps in the formation of melanosomes, the subcellular organelles of melanocytes in which melanin pigments are synthesized and stored. In melanosome precursor organelles, proteolytic fragments of Pmel17 form insoluble, amyloid-like fibrils upon which melanins are deposited during melanosome maturation. The mechanism(s) by which Pmel17 becomes competent to form amyloid are not fully understood. To better understand how amyloid formation is regulated, we have defined the domains within Pmel17 that promote fibril formation in vitro. Using purified recombinant fragments of Pmel17, we show that two regions, an N-terminal domain of unknown structure and a downstream domain with homology to a polycystic kidney disease-1 repeat, efficiently form amyloid in vitro. Analyses of fibrils formed in melanocytes confirm that the polycystic kidney disease-1 domain forms at least part of the physiological amyloid core. Interestingly, this same domain is also required for the intracellular trafficking of Pmel17 to multivesicular compartments within which fibrils begin to form. Although a domain of imperfect repeats (RPT) is required for fibril formation in vivo and is a component of fibrils in melanosomes, RPT is not necessary for fibril formation in vitro and in isolation is unable to adopt an amyloid fold in a physiologically relevant time frame. These data define the structural core of Pmel17 amyloid, imply that the RPT domain plays a regulatory role in timing amyloid conversion, and suggest that fibril formation might be physically linked with multivesicular body sorting.

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confidence: 62%

N-terminal Domains Elicit Formation of Functional Pmel17 Amyloid Fibrils

Watt

Niel

Fowler

et al. 2009

Journal of Biological Chemistry

102

154

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“…5C,D) and represents the repeat domain of the PMEL protein (Hoashi et al 2006). An autosomal dominant C>T missense mutation in exon 11 changes the second amino acid in the cytoplasmic region of PMEL in exon 11 (Arg618Cys) and shows 100% concordance with the Silver coat color in horses (Brunberg et al 2006). Thus, we investigated whether the CNV in exon 6 of the PMEL gene corre- lated with the associated mutation and the Silver coat color.…”

Section: Mendelian Genes Affected By Cnvsmentioning

confidence: 99%

“…Each gene was differentially affected by a CNV, by either involving a duplicated or deleted portion of an exon, an entire exon or entire exons, a UTR, a gene, or multiple genes. We further investigated two of these CNVs (PMEL and BMPR1B), because of the association of these genes with known phenotypes (Brunberg et al 2006;Chu et al 2007). …”

Section: Mendelian Genes Affected By Cnvsmentioning

confidence: 99%

Identification of copy number variants in horses

et al. 2012

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Copy number variants (CNVs) represent a substantial source of genetic variation in mammals. However, the occurrence of CNVs in horses and their subsequent impact on phenotypic variation is unknown. We performed a study to identify CNVs in 16 horses representing 15 distinct breeds (Equus caballus) and an individual gray donkey (Equus asinus) using a wholeexome tiling array and the array comparative genomic hybridization methodology. We identified 2368 CNVs ranging in size from 197 bp to 3.5 Mb. Merging identical CNVs from each animal yielded 775 CNV regions (CNVRs), involving 1707 protein-and RNA-coding genes. The number of CNVs per animal ranged from 55 to 347, with median and mean sizes of CNVs of 5.3 kb and 99.4 kb, respectively. Approximately 6% of the genes investigated were affected by a CNV. Biological process enrichment analysis indicated CNVs primarily affected genes involved in sensory perception, signal transduction, and metabolism. CNVs also were identified in genes regulating blood group antigens, coat color, fecundity, lactation, keratin formation, neuronal homeostasis, and height in other species. Collectively, these data are the first report of copy number variation in horses and suggest that CNVs are common in the horse genome and may modulate biological processes underlying different traits observed among horses and horse breeds.

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“…4). The requirement of Pmel17 for the generation of functional melanin has been shown in a number of different organisms, because, for example, certain point mutations in the Pmel17/silver gene result in hypopigmentation phenotypes (5)(6)(7). The most characteristic domain within Pmel17 is a specific lumenal proline/serine/threonine rich repeat domain (see Fig.…”

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confidence: 99%

Formation of Pmel17 Amyloid Is Regulated by Juxtamembrane Metalloproteinase Cleavage, and the Resulting C-terminal Fragment Is a Substrate for γ-Secretase

Kummer

Maruyama

Huelsmann

et al. 2009

Journal of Biological Chemistry

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The formation of insoluble cross ␤-sheet amyloid is pathologically associated with disorders such as Alzheimer, Parkinson, and Huntington diseases. One exception is the nonpathological amyloid derived from the protein Pmel17 within melanosomes to generate melanin pigment. Here we show that the formation of insoluble M␣C intracellular fragments of Pmel17, which are the direct precursors to Pmel17 amyloid, depends on a novel juxtamembrane cleavage at amino acid position 583 between the furin-like proprotein convertase cleavage site and the transmembrane domain. The resulting Pmel17 C-terminal fragment is then processed by the ␥-secretase complex to release a shortlived intracellular domain fragment. Thus, by analogy to the Notch receptor, we designate this cleavage the S2 cleavage site, whereas ␥-secretase mediates proteolysis at the intramembrane S3 site. Substitutions or deletions at this S2 cleavage site, the use of the metalloproteinase inhibitor TAPI-2, as well as small interfering RNA-mediated knock-down of the metalloproteinases ADAM10 and 17 reduced the formation of insoluble Pmel17 fragments. These results demonstrate that the release of the Pmel17 ectodomain, which is critical for melanin amyloidogenesis, is initiated by S2 cleavage at a juxtamembrane position.Folding of proteins is a highly regulated process ensuring their correct three-dimensional structure. Under pathological circumstances, a soluble protein can be folded into highly stable cross ␤-sheet amyloid structures, which are believed to play pathological roles in disorders such as Alzheimer, Parkinson, and Huntington diseases. An exception to this general concept is the physiological amyloid structure of the melanosomal matrix formed by the protein Pmel17. Melanosomes are lysosome-related organelles that contain pigment granules (melanin) in melanocytes and retinal epithelial cells (reviewed in Ref. 1). Melanogenesis is believed to proceed through several sequential maturation steps, classified by melanosomes from stage I to stage IV. Maturation of stage II melanosomes requires the formation of Pmel17 intralumenal fibers (2, 3).Pmel17 (also called gp100, ME20, RPE1, or silver) is a type I transmembrane glycoprotein of up to 668 amino acids in humans (reviewed in Ref. 4). The requirement of Pmel17 for the generation of functional melanin has been shown in a number of different organisms, because, for example, certain point mutations in the Pmel17/silver gene result in hypopigmentation phenotypes (5-7). The most characteristic domain within Pmel17 is a specific lumenal proline/serine/threonine rich repeat domain (see Fig. 1A), that is imperfectly repeated 13 times in the M␣ fragment. Importantly, deletion of the rich repeat domain results in a complete loss of fibril formation, pointing to the requirement of Pmel17, and especially the rich repeat domain, in melanin formation (8). Pmel17 exists in different isoforms generated by alternative splicing. Pmel17-i 2 is the most abundant isoform, whereas the Pmel17-l isoform contains a 7-amino acid in...

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A missense mutation in PMEL17 is associated with the Silver coat color in the horse

Cited by 140 publications

References 29 publications

N-terminal Domains Elicit Formation of Functional Pmel17 Amyloid Fibrils

N-terminal Domains Elicit Formation of Functional Pmel17 Amyloid Fibrils

Identification of copy number variants in horses

Formation of Pmel17 Amyloid Is Regulated by Juxtamembrane Metalloproteinase Cleavage, and the Resulting C-terminal Fragment Is a Substrate for γ-Secretase

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