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PLoS One ; 17(11): e0277284, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36374931


Numerous single gene mutations identified in humans and mice result in nail deformities with many similarities between the species. A spontaneous, autosomal, recessive mutation called witch nails (whnl) is described here where the distal nail matrix and nail bed undergo degenerative changes resulting in formation of an abnormal nail plate causing mice to develop long, curved nails. This mutation arose spontaneously in a colony of MRL/MpJ-Faslpr/J at The Jackson Laboratory. Homozygous mutant mice are recognizable by 8 weeks of age by their long, curved nails. The whnl mutation, mapped on Chromosome 15, is due to a 7-bp insertion identified in the 3' region of exon 9 in the Krt90 gene (formerly Riken cDNA 4732456N10Rik), and is predicted to result in a frameshift that changes serine 476 to arginine and subsequently introduces 36 novel amino acids into the protein before a premature stop codon (p. Ser476ArgfsTer36). By immunohistochemistry the normal KRT90 protein is expressed in the nail matrix and nail bed in control mice where lesions are located in mutant mice. Immunoreactivity toward equine KRT124, the ortholog of mouse KRT90, is restricted to the hoof lamellae (equine hoof wall and lamellae are homologous to the mouse nail plate and nail bed) and the mouse nail bed. Equine laminitis lesions are similar to those observed in this mutant mouse suggesting that the latter may be a useful model for hoof and nail diseases. This first spontaneous mouse mutation affecting the novel Krt90 gene provides new insight into the normal regulation of the molecular pathways of nail development.

Doenças da Unha , Unhas Malformadas , Animais , Camundongos , Crescimento e Desenvolvimento , Cavalos , Mutação , Doenças da Unha/genética , Unhas/química , Unhas Malformadas/genética
Genome Res ; 25(7): 948-57, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25917818


Spontaneously arising mouse mutations have served as the foundation for understanding gene function for more than 100 years. We have used exome sequencing in an effort to identify the causative mutations for 172 distinct, spontaneously arising mouse models of Mendelian disorders, including a broad range of clinically relevant phenotypes. To analyze the resulting data, we developed an analytics pipeline that is optimized for mouse exome data and a variation database that allows for reproducible, user-defined data mining as well as nomination of mutation candidates through knowledge-based integration of sample and variant data. Using these new tools, putative pathogenic mutations were identified for 91 (53%) of the strains in our study. Despite the increased power offered by potentially unlimited pedigrees and controlled breeding, about half of our exome cases remained unsolved. Using a combination of manual analyses of exome alignments and whole-genome sequencing, we provide evidence that a large fraction of unsolved exome cases have underlying structural mutations. This result directly informs efforts to investigate the similar proportion of apparently Mendelian human phenotypes that are recalcitrant to exome sequencing.

Exoma , Mutação , Animais , Feminino , Doenças Genéticas Inatas/genética , Ligação Genética , Variação Genética , Estudo de Associação Genômica Ampla , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Masculino , Camundongos , Fenótipo , Reprodutibilidade dos Testes
Acad J Xian Jiaotong Univ ; 25(3): 209-212, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21179397


OBJECTIVE: to map a mouse deafness gene, identify the underlying mutation and develop a mouse model for human deafness. METHODS: genetic linkage cross and genome scan were used to map a novel mutation named hypoplasia of the membranous labyrinth (hml), which causes hearing loss in mutant mice. RESULTS: 1. hml was mapped on mouse Chr 10 (~43 cM from the centromere) suggests that the homologous human gene is on 12q22-q24, which was defined on the basis of known mouse-human homologies (OMIM, 2004). 2. This study has generated 25 polymorphic microsatellite markers, placed 3 known human genes in the correct order in a high-resolution mouse map and narrowed the hml candidate gene region to a 500kb area.

Genomics ; 81(1): 6-14, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12573256


In the outcrossing of a new recessive mouse mutation causing hair loss, a new wavy-coated phenotype appeared. The two distinct phenotypes were shown to be alternative manifestations of the same gene mutation and attributable to a single modifier locus. The new mutation, curly bare (cub), was mapped to distal Chr 11 and the modifier (mcub) was mapped to Chr 5. When homozygous for the recessive mcub allele, cub/cub mice appear hairless. A single copy of the dominant Mcub allele confers a full, curly coat in cub/cub mice. Reciprocal transfer of full-thickness skin grafts between mutant and control animals showed that the skin phenotype was tissue autonomous. The hairless cub/cub mcub/mcub mice show normal contact sensitivity responses to oxazolone. The similarity of the wavy coat phenotype to those of Tgfa and Egfr mutations and the map positions of cub and mcub suggest candidate genes that interact in the EGF receptor signal transduction pathway.

Mapeamento Cromossômico , Genes Reguladores/genética , Cabelo/anormalidades , Animais , Cruzamentos Genéticos , Cabelo/fisiologia , Hipersensibilidade/genética , Camundongos , Transplante de Pele