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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
Exp Dermatol ; 28(4): 383-390, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30074290


In a large-scale ageing study, 30 inbred mouse strains were systematically screened for histologic evidence of lesions in all organ systems. Ten strains were diagnosed with similar nail abnormalities. The highest frequency was noted in NON/ShiLtJ mice. Lesions identified fell into two main categories: acute to chronic penetration of the third phalangeal bone through the hyponychium with associated inflammation and bone remodelling or metaplasia of the nail matrix and nail bed associated with severe orthokeratotic hyperkeratosis replacing the nail plate. Penetration of the distal phalanx through the hyponychium appeared to be the initiating feature resulting in nail abnormalities. The accompanying acute to subacute inflammatory response was associated with osteolysis of the distal phalanx. Evaluation of young NON/ShiLtJ mice revealed that these lesions were not often found, or affected only one digit. The only other nail unit abnormality identified was sporadic subungual epidermoid inclusion cysts which closely resembled similar lesions in human patients. These abnormalities, being age-related developments, may have contributed to weight loss due to impacts upon feeding and should be a consideration for future research due to the potential to interact with other experimental factors in ageing studies using the affected strains of mice.

Envelhecimento/patologia , Unhas Malformadas/patologia , Falanges dos Dedos do Pé/patologia , Animais , Remodelação Óssea , Estudos Transversais , Cisto Epidérmico/complicações , Feminino , Inflamação/etiologia , Queratina-1/metabolismo , Queratina-10/metabolismo , Ceratose/etiologia , Estudos Longitudinais , Masculino , Metaplasia/patologia , Camundongos , Camundongos Endogâmicos , Unhas Malformadas/etiologia , Unhas Malformadas/metabolismo
PLoS One ; 13(10): e0205775, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30372477


In a large scale screen for skin, hair, and nail abnormalities in null mice generated by The Jackson Laboratory's KOMP center, homozygous mutant Far2tm2b(KOMP)Wtsi/2J (hereafter referrred to as Far2-/-) mice were found to develop focal areas of alopecia as they aged. As sebocytes matured in wildtype C57BL/NJ mice they became pale with fine, uniformly sized clear lipid containing vacuoles that were released when sebocytes disintegrated in the duct. By contrast, the Far2-/- null mice had sebocytes that were similar within the gland but become brightly eosinophilic when the cells entered the sebaceous gland duct. As sebocytes disintegrated, their contents did not readily dissipate. Scattered throughout the dermis, and often at the dermal hypodermal fat junction, were dystrophic hair follicles or ruptured follicles with a foreign body granulomatous reaction surrounding free hair shafts (trichogranuloma). The Meibomian and clitoral glands (modified sebaceous glands) of Far2-/- mice showed ducts dilated to various degrees that were associated with mild changes in the sebocytes as seen in the truncal skin. Skin surface lipidomic analysis revealed a lower level of wax esters, cholesterol esters, ceramides, and diacylglycerols compared to wildtype control mice. Similar changes were described in a number of other mouse mutations that affected the sebaceous glands resulting in primary cicatricial alopecia.

Aldeído Oxirredutases/genética , Alopecia/genética , Cicatriz/genética , Folículo Piloso/patologia , Glândulas Sebáceas/patologia , Alopecia/patologia , Animais , Cicatriz/patologia , Modelos Animais de Doenças , Feminino , Humanos , Metabolismo dos Lipídeos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Glândulas Sebáceas/citologia
J Invest Dermatol ; 123(6): 1001-11, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15610506


Nude mice have a mutation in the transcription factor Foxn1(nu), resulting in downregulation of hair keratins. Although hair follicles develop normally, the hair fibers become structurally weak, curl, and break off at the surface. Nails in nude mice are deformed, based on alterations of the onychocyte differentiation process. Elemental microanalysis of the nail plate reveals marked decreases in sulfur concentrations in the nude mouse nail plates. Immunohistochemistry shows a lack of keratin 1 expression in terminally differentiating keratinocytes of the nail matrix. Instead, the typical differentiation process of the matrix is altered toward an epidermis-like differentiation pattern, comprising the production of filaggrin-containing keratohyalin granules in cells resembling those of the stratum granulosum, which are never observed in normally haired mice. The nail plate has diffuse basophilic stippling. It is thinner than normal, weak, and in most Foxn1(nu)/Foxn1(nu) mice breaks where it separates from the hyponychium. These studies indicate that the Foxn1(nu) mutated gene has effects beyond downregulating keratin expression, including changes in filaggrin expression, and is critical for normal onycholemmal differentiation. The nails of nude mice provide new insights into the molecular controls of onychocyte differentiation, and they offer a useful model to investigate the pathogenesis of nail hypergranulosis, a common feature in human nail diseases.

Proteínas de Ligação a DNA/fisiologia , Casco e Garras/fisiopatologia , Queratinócitos/fisiologia , Unhas Malformadas/patologia , Unhas Malformadas/fisiopatologia , Fatores de Transcrição/fisiologia , Animais , Diferenciação Celular , Proteínas de Ligação a DNA/genética , Regulação para Baixo , Células Epiteliais/citologia , Proteínas Filagrinas , Fatores de Transcrição Forkhead , Regulação da Expressão Gênica , Casco e Garras/patologia , Casco e Garras/ultraestrutura , Integrinas/metabolismo , Proteínas de Filamentos Intermediários/metabolismo , Queratina-15 , Queratina-5 , Queratinócitos/patologia , Queratinócitos/ultraestrutura , Queratinas/metabolismo , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Microscopia Eletrônica de Varredura , Unhas Malformadas/genética , Mucosa Olfatória/citologia , Palato/citologia , Enxofre/metabolismo , Papilas Gustativas/citologia , Dente/citologia , Fatores de Transcrição/genética