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2.
Nat Genet ; 27(1): 103-7, 2001 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-11138008

RESUMO

Mouse chromosome 10 harbors several loci associated with hearing loss, including waltzer (v), modifier-of deaf waddler (mdfw) and Age-related hearing loss (Ahl). The human region that is orthologous to the mouse 'waltzer' region is located at 10q21-q22 and contains the human deafness loci DFNB12 and USH1D). Numerous mutations at the waltzer locus have been documented causing erratic circling and hearing loss. Here we report the identification of a new gene mutated in v. The 10.5-kb Cdh23 cDNA encodes a very large, single-pass transmembrane protein, that we have called otocadherin. It has an extracellular domain that contains 27 repeats; these show significant homology to the cadherin ectodomain. In v(6J), a GT transversion creates a premature stop codon. In v(Alb), a CT exchange generates an ectopic donor splice site, effecting deletion of 119 nucleotides of exonic sequence. In v(2J), a GA transition abolishes the donor splice site, leading to aberrant splice forms. All three alleles are predicted to cause loss of function. We demonstrate Cdh23 expression in the neurosensory epithelium and show that during early hair-cell differentiation, stereocilia organization is disrupted in v(2J) homozygotes. Our data indicate that otocadherin is a critical component of hair bundle formation. Mutations in human CDH23 cause Usher syndrome type 1D and thus, establish waltzer as the mouse model for USH1D.


Assuntos
Caderinas/genética , Células Ciliadas Auditivas Internas/patologia , Perda Auditiva Neurossensorial/genética , Mutação/genética , Sequência de Aminoácidos , Animais , Percepção Auditiva/fisiologia , Sequência de Bases , Caderinas/química , Caderinas/metabolismo , Clonagem Molecular , Cóclea/metabolismo , Análise Mutacional de DNA , Modelos Animais de Doenças , Células Ciliadas Auditivas Internas/metabolismo , Células Ciliadas Auditivas Internas/fisiopatologia , Células Ciliadas Auditivas Internas/ultraestrutura , Audição/fisiologia , Perda Auditiva Neurossensorial/patologia , Testes Auditivos , Hibridização In Situ , Camundongos , Camundongos Endogâmicos , Camundongos Mutantes , Microscopia Eletrônica de Varredura , Dados de Sequência Molecular , RNA Mensageiro/análise , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Síndrome
3.
Mech Dev ; 91(1-2): 175-87, 2000 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-10704842

RESUMO

During the initial stages of vertebrate retinogenesis, cells of the optic vesicle adopt one of two alternate cell fates. Cells in the distal-most part of the vesicle, immediately beneath the surface ectoderm, undergo neural differentiation; cells in the proximal part differentiate into retinal pigmented epithelial cells. The mechanisms that establish this pattern of differentiation are poorly understood. In the mouse embryo, Msx2, a homeobox-containing transcription factor, is expressed in cells of the optic vesicle that will form the neural retina, whilst the developing retinal pigmented epithelium (RPE) does not express this gene. Msx2 could therefore be involved in patterning the optic vesicle into neural and pigmented domains. To explore this possibility we ectopically expressed mouse Msx2 in cultures of chick RPE cells. Compared with cultures transfected with a control construct, Msx2-transfected cultures contained fewer cells expressing the RPE marker, Mitf, and more cells expressing class III beta-tubulin, a neuronal marker. In addition a small proportion of Msx2-transfected cells acquired a neural-like morphology. These results show that Msx2 can suppress the differentiated state of RPE cells and promote their differentiation into neural cell types. We suggest that Msx2 may pattern the optic vesicle into neural and pigmented domains by affecting the balance between RPE and neural retina differentiation.


Assuntos
Padronização Corporal , Proteínas de Ligação a DNA/fisiologia , Fatores de Transcrição , Animais , Galinhas , Técnicas de Cultura , Proteínas de Ligação a DNA/biossíntese , Proteínas de Ligação a DNA/genética , Expressão Gênica , Proteínas de Homeodomínio/genética , Fator de Transcrição MSX1 , Camundongos , Fator de Transcrição Associado à Microftalmia , Neurônios/citologia , Neurônios/metabolismo , Epitélio Pigmentado Ocular/embriologia , Retina/citologia , Retina/embriologia , Regulação para Cima
4.
Curr Opin Genet Dev ; 9(3): 309-14, 1999 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-10377287

RESUMO

Remarkable progress has been made over the past few years in the field of hereditary deafness. To date, mutations in at least 35 genes are known to cause hearing loss. We are now beginning to understand the function of many of these genes, which affect diverse aspects of ear development and function.


Assuntos
Surdez/genética , Células Ciliadas Auditivas/fisiopatologia , Mutação , Endolinfa , Homeostase , Humanos , Melanócitos/citologia
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