title: A homozygous single-base deletion in MLPH causes the dilute coat color phenotype in the domestic cat.
abstract: Three proteins have been described in humans and mice as being essential for even distribution, transport, and translocation of pigment granules, with defects in these molecules giving rise to lighter skin/coat color. The dilute phenotype in domestic cats affects both eumelanin and phaeomelanin pigment pathways; for example, black pigmentation combined with dilute appears gray and orange pigments appear cream. The dilute pigmentation segregates as a fully penetrant, autosomal recessive trait. We conducted classical linkage mapping with microsatellites in a large multigeneration pedigree of domestic cats and detected tight linkage for dilute on cat chromosome C1 (theta=0.08, LOD=10.81). Fine-mapping identified a genomic region exhibiting conserved synteny to human chromosome 2, which included one of the three dilute candidate genes, melanophilin (MLPH). Sequence analysis in dilute cats identified a single base pair deletion in exon 2 of MLPH transcripts that introduces a stop codon 11 amino acids downstream, resulting in the truncation of the bulk of the MLPH protein. The occurrence of this homozygous variant in 97 unrelated dilute cats representing 26 cat breeds and random-bred cats, along with 89 unrelated wild-type cats representing 29 breeds and random-bred cats, supports the finding that dilute is caused by this single mutation in MLPH (p<0.00001). Single-nucleotide polymorphism analyses in dilute individuals identified a single haplotype in dilute cats, suggesting that a single mutation event in MLPH gave rise to dilute in domestic cats.
authors.affiliation: Laboratory of Genomic Diversity, National Cancer Institute, Building 560, Room 11-38, Fort Detrick, Frederick, MD 21702, USA. Electronic address: ishiday@ncifcrf.gov.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Ishida
authors.affiliation: Laboratory of Genomic Diversity, National Cancer Institute, Building 560, Room 11-38, Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Victor A
authors.initials: VA
authors.lastname: David
authors.affiliation: Centro de Biologia Genômica e Molecular, PUCRS, Porto Alegre, RS 90619-900, Brazil.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Eizirik
authors.affiliation: National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20894, USA.
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Schäffer
authors.affiliation: Advanced Biomedical Computing Center, SAIC-Frederick, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Beena A
authors.initials: BA
authors.lastname: Neelam
authors.affiliation: Laboratory of Genomic Diversity, SAIC-Frederick, National Cancer Institute, Frederick, MD 21702, USA.
authors.forename: Melody E
authors.initials: ME
authors.lastname: Roelke
authors.affiliation: Nestlé Purina PetCare; St. Louis, MO 63134, USA.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Hannah
authors.affiliation: Laboratory of Genomic Diversity, National Cancer Institute, Building 560, Room 11-38, Fort Detrick, Frederick, MD 21702, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: O'Brien
authors.affiliation: Laboratory of Genomic Diversity, National Cancer Institute, Building 560, Room 11-38, Fort Detrick, Frederick, MD 21702, USA. Electronic address: raymond@ncifcrf.gov.
authors.forename: Marilyn
authors.initials: M
authors.lastname: Menotti-Raymond
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000818:Animals; D000829:Animals, Domestic / Q000235:genetics; D001483:Base Sequence; D002415:Cats / Q000235:genetics*; D002874:Chromosome Mapping / Q000662:veterinary*; D017353:Gene Deletion; D006200:Hair Color / Q000235:genetics*; D006720:Homozygote; D007438:Introns / Q000235:genetics; D018895:Microsatellite Repeats / Q000235:genetics; D008969:Molecular Sequence Data; D010641:Phenotype
chemical_list: D048868:Adaptor Proteins, Signal Transducing