RESUMO
Distinct classes of SOX10 mutations result in peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease, collectively known as PCWH. Meanwhile, SOX10 haploinsufficiency caused by allelic loss-of-function mutations leads to a milder non-neurological disorder, Waardenburg-Hirschsprung disease. The cellular pathogenesis of more complex PCWH phenotypes in vivo has not been thoroughly understood. To determine the pathogenesis of PCWH, we have established a transgenic mouse model. A known PCWH-causing SOX10 mutation, c.1400del12, was introduced into mouse Sox10-expressing cells by means of bacterial artificial chromosome (BAC) transgenesis. By crossing the multiple transgenic lines, we examined the effects produced by various copy numbers of the mutant transgene. Within the nervous systems, transgenic mice revealed a delay in the incorporation of Schwann cells in the sciatic nerve and the terminal differentiation of oligodendrocytes in the spinal cord. Transgenic mice also showed defects in melanocytes presenting as neurosensory deafness and abnormal skin pigmentation, and a loss of the enteric nervous system. Phenotypes in each lineage were more severe in mice carrying higher copy numbers, suggesting a gene dosage effect for mutant SOX10. By uncoupling the effects of gain-of-function and haploinsufficiency in vivo, we have demonstrated that the effect of a PCWH-causing SOX10 mutation is solely pathogenic in each SOX10-expressing cellular lineage in a dosage-dependent manner. In both the peripheral and central nervous systems, the primary consequence of SOX10 mutations is hypomyelination. The complex neurological phenotypes in PCWH patients likely result from a combination of haploinsufficiency and additive dominant effect.
Assuntos
Doenças Desmielinizantes/genética , Doença de Hirschsprung/genética , Fatores de Transcrição SOXE/genética , Síndrome de Waardenburg/genética , Animais , Encéfalo/anormalidades , Encéfalo/ultraestrutura , Corpo Caloso/ultraestrutura , Doenças Desmielinizantes/embriologia , Doenças Desmielinizantes/patologia , Modelos Animais de Doenças , Genes Dominantes , Haploinsuficiência , Doença de Hirschsprung/embriologia , Doença de Hirschsprung/patologia , Humanos , Camundongos , Camundongos Transgênicos , Crista Neural/anormalidades , Fenótipo , Células de Schwann/patologia , Nervo Isquiático/ultraestrutura , Síndrome de Waardenburg/embriologia , Síndrome de Waardenburg/patologiaRESUMO
Haploinsufficiency for the transcription factor SOX10 is associated with the pigmentary deficiencies of Waardenburg syndrome (WS) and is modeled in Sox10 haploinsufficient mice (Sox10(LacZ/+)). As genetic background affects WS severity in both humans and mice, we established an N-ethyl-N-nitrosourea (ENU) mutagenesis screen to identify modifiers that increase the phenotypic severity of Sox10(LacZ/+) mice. Analysis of 230 pedigrees identified three modifiers, named modifier of Sox10 neurocristopathies (Mos1, Mos2 and Mos3). Linkage analysis confirmed their locations on mouse chromosomes 13, 4 and 3, respectively, within regions distinct from previously identified WS loci. Positional candidate analysis of Mos1 identified a truncation mutation in a hedgehog(HH)-signaling mediator, GLI-Kruppel family member 3 (Gli3). Complementation tests using a second allele of Gli3 (Gli3(Xt-J)) confirmed that a null mutation of Gli3 causes the increased hypopigmentation in Sox10(LacZ/+);Gli3(Mos1/)(+) double heterozygotes. Early melanoblast markers (Mitf, Sox10, Dct, and Si) are reduced in Gli3(Mos1/)(Mos1) embryos, indicating that loss of GLI3 signaling disrupts melanoblast specification. In contrast, mice expressing only the GLI3 repressor have normal melanoblast specification, indicating that the full-length GLI3 activator is not required for specification of neural crest to the melanocyte lineage. This study demonstrates the feasibility of sensitized screens to identify disease modifier loci and implicates GLI3 and other HH signaling components as modifiers of human neurocristopathies.
Assuntos
Proteínas de Ligação a DNA/metabolismo , Proteínas de Grupo de Alta Mobilidade/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Mutagênese , Proteínas do Tecido Nervoso/metabolismo , Crista Neural/fisiopatologia , Fatores de Transcrição/metabolismo , Síndrome de Waardenburg/metabolismo , Síndrome de Waardenburg/fisiopatologia , Animais , Sequência de Bases , Diferenciação Celular , Mapeamento Cromossômico , Códon sem Sentido , Proteínas de Ligação a DNA/genética , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/fisiopatologia , Etilnitrosoureia/farmacologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Teste de Complementação Genética , Proteínas de Grupo de Alta Mobilidade/genética , Humanos , Fatores de Transcrição Kruppel-Like/genética , Masculino , Melanócitos/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Mutagênicos/farmacologia , Proteínas do Tecido Nervoso/genética , Crista Neural/efeitos dos fármacos , Crista Neural/embriologia , Crista Neural/metabolismo , Pigmentação , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Fatores de Transcrição SOXE , Fatores de Transcrição/genética , Síndrome de Waardenburg/embriologia , Síndrome de Waardenburg/genética , Proteína Gli3 com Dedos de ZincoRESUMO
Recent years have seen the identification of a complex network of interacting genes that regulates embryonic development of melanocytes, and many different genetic disorders of melanocyte development of both humans and the laboratory mouse have now been associated with abnormalities of these regulatory genes. Disorders of melanocyte development are characterized by heterogeneous distribution of pigmentation, so-called 'white spotting,' typified by piebaldism and Waardenburg syndrome. It is now clear that these disorders of pigment cell development represent a subgroup of the neurocristopathies, involving defects of various neural crest cell lineages that include melanocytes, but also involving many other tissues derived from the neural crest.
Assuntos
Melanócitos/patologia , Piebaldismo/patologia , Transtornos da Pigmentação/patologia , Síndrome de Waardenburg/patologia , Animais , Linhagem da Célula , Humanos , Camundongos , Crista Neural/anormalidades , Crista Neural/embriologia , Crista Neural/patologia , Piebaldismo/embriologia , Piebaldismo/genética , Transtornos da Pigmentação/embriologia , Transtornos da Pigmentação/genética , Pigmentação da Pele/genética , Síndrome de Waardenburg/embriologia , Síndrome de Waardenburg/genéticaRESUMO
Pax genes encode transcription factors sharing a highly conserved sequence, the paired box. Their temporally and spatially restricted expression patterns during development indicate that Pax genes are involved in important steps of nervous system formation. Mutations in Pax genes have been correlated with three mouse mutants (undulated, splotch, small eye) and two human diseases (Waardenburg syndrome, aniridia). Recent data demonstrated that deregulation of Pax genes contributes to tumor formation.
Assuntos
Desenvolvimento Embrionário e Fetal/genética , Fatores de Transcrição/genética , Animais , Aniridia/embriologia , Aniridia/genética , Sistema Nervoso Central/embriologia , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Camundongos , Mutação , Neoplasias/etiologia , Neoplasias/genética , Gravidez , Síndrome de Waardenburg/embriologia , Síndrome de Waardenburg/genéticaRESUMO
Waardenburg syndrome (WS) is an autosomal dominant disorder characterised by pigmentary abnormalities and sensorineural deafness. It is subcategorised into type 1 (WS1) and type 2 (WS2) on the basis of the presence (WS1) or absence (WS2) of dystopia canthorum. WS1 is always caused by mutations in the PAX3 gene, whereas WS2 is caused by mutations in the microphthalmia (MITF) gene in some but not all families. An association of WS symptoms with Hirschsprung disease (HSCR) has been reported in many families. We report here a patient with characteristics of WS2 and a de novo interstitial deletion of chromosome 13q. We also describe a family with two sibs who have both WS2 and HSCR. In this family, all possible genes for WS and HSCR, but not chromosome 13q, could be excluded. As an association between chromosome 13q and HSCR/WS has been reported previously, these data suggest that there is a gene on chromosome 13q that is responsible for WS or HSCR or both.
Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 13/ultraestrutura , Proteínas de Ligação a DNA/genética , Genes Homeobox , Doença de Hirschsprung/genética , Crista Neural/anormalidades , Receptores de Endotelina/genética , Fatores de Transcrição , Síndrome de Waardenburg/genética , Animais , Mapeamento Cromossômico , Cromossomos Humanos Par 3 , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Heterogeneidade Genética , Humanos , Recém-Nascido , Escore Lod , Masculino , Camundongos , Camundongos Mutantes , Fator de Transcrição Associado à Microftalmia , Repetições de Microssatélites , Fator de Transcrição PAX3 , Fatores de Transcrição Box Pareados , Receptor de Endotelina B , Especificidade da Espécie , Síndrome de Waardenburg/classificação , Síndrome de Waardenburg/embriologiaAssuntos
Orelha/embriologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Animais , Encéfalo/embriologia , Nervos Cranianos/embriologia , Orelha/anormalidades , Genes Homeobox , Camundongos , Camundongos Mutantes/embriologia , Camundongos Mutantes/genética , Camundongos Mutantes Neurológicos/embriologia , Camundongos Mutantes Neurológicos/genética , Microscopia Eletrônica de Varredura , Morfogênese/genética , Fenótipo , Síndrome de Waardenburg/embriologia , Síndrome de Waardenburg/genéticaRESUMO
An 18 year old single Jewish woman with the Waardenburg syndrome and absence of a vagina and right sided adnexa uteri is reported. Other congenital malformations associated with the Waardenburg syndrome are mentioned and it is postulated that they may be the result of an altered invasion of neurones or altered neurones in certain organ systems early in embryogenesis.
Assuntos
Anormalidades Múltiplas/embriologia , Anexos Uterinos/anormalidades , Vagina/anormalidades , Síndrome de Waardenburg/embriologia , Adolescente , Feminino , HumanosRESUMO
The striking parallel between the melanin pigmentary abnormalities of the hair and skin in piebaldism, Waardenburg's syndrome, piebaldism with deafness, and piebaldism or Waardenburg's syndrome with aganglionosis of the gut suggests that all these disorders belong to the same category. At present, the most logical way to link these syndromes is to consider them the results of defective development of the neural crest. The reason that in certain circumstances only melanoblasts are affected whereas in other situations other neural crest derivatives also are involved is not yet clear. In addition, some features, such as the upper limb abnormalities observed in Klein's syndrome, are not explained by a neural crest defect. Our knowledge of the interaction between the neural crest and neighboring structures closely related to it during embryonic life is limited. Some clues allowing us to better understand these complex syndromes combining depigmentation of hair and skin will come from future research in this field.
Assuntos
Transtornos da Pigmentação/embriologia , Animais , Doenças do Cabelo/patologia , Humanos , Melanócitos/fisiologia , Crista Neural/fisiologia , Transtornos da Pigmentação/patologia , Transtornos da Pigmentação/fisiopatologia , Pele/patologia , Pigmentação da Pele , Síndrome de Waardenburg/embriologia , Síndrome de Waardenburg/patologiaRESUMO
A patient with Waardenburg syndrome type II associated with Hirschsprung megacolon and Marcus Gunn ptosis is presented. It is suggested that these different anomalies are manifestations of the same neurocrestopathy.
Assuntos
Anormalidades Múltiplas/embriologia , Blefaroptose/embriologia , Doença de Hirschsprung/embriologia , Crista Neural , Síndrome de Waardenburg/embriologia , Adolescente , Feminino , HumanosAssuntos
Transtornos da Audição/genética , Transtornos da Pigmentação/genética , Transtornos da Visão/genética , Adulto , Animais , Doenças do Gato/embriologia , Gatos , Doenças do Cão/embriologia , Cães , Feminino , Transtornos da Audição/embriologia , Humanos , Transtornos da Pigmentação/embriologia , Transtornos da Visão/embriologia , Síndrome de Waardenburg/embriologiaAssuntos
Anormalidades Múltiplas/embriologia , Megacolo/embriologia , Crista Neural/fisiologia , Neoplasias da Glândula Tireoide/embriologia , Síndrome de Waardenburg/embriologia , Animais , Carcinoma/embriologia , Movimento Celular , Embrião de Galinha , Modelos Animais de Doenças , Face/anormalidades , Humanos , Crista Neural/ultraestrutura , RatosRESUMO
The inherited syndrome of irregular depigmentation of the skin, hair, iris and ocular fundus with associated congenital defects of the inner ear resulting in hearing loss or deafness occurs in several different species including man. The "deaf white cat" provides a useful model of this syndrome. There are several genetic mechanisms involved. The deafness is sometimes progressive in the newborn period. The pathology suggests involvement of the neural crest.