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1.
Am J Hum Genet ; 89(6): 773-81, 2011 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-22152679

RESUMO

Inherited dental malformations constitute a clinically and genetically heterogeneous group of disorders. Here, we report on a severe developmental dental defect that results in a dentin dysplasia phenotype with major microdontia, oligodontia, and shape abnormalities in a highly consanguineous family. Homozygosity mapping revealed a unique zone on 6q27-ter. The two affected children were found to carry a homozygous mutation in SMOC2. Knockdown of smoc2 in zebrafish showed pharyngeal teeth that had abnormalities reminiscent of the human phenotype. Moreover, smoc2 depletion in zebrafish affected the expression of three major odontogenesis genes: dlx2, bmp2, and pitx2.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Mapeamento Cromossômico , Displasia da Dentina/genética , Exoma , Homozigoto , Análise de Sequência de DNA , Dente/crescimento & desenvolvimento , Proteínas Adaptadoras de Transdução de Sinal , Animais , Proteínas de Transporte/genética , Criança , Pré-Escolar , Cromossomos Humanos Par 6 , Consanguinidade , Displasia da Dentina/diagnóstico , Feminino , Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Estudos de Associação Genética , Humanos , Camundongos , Dados de Sequência Molecular , Proteínas de Neoplasias/genética , Linhagem , Peixe-Zebra/genética , Peixe-Zebra/crescimento & desenvolvimento
2.
Arterioscler Thromb Vasc Biol ; 31(4): 842-50, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21273561

RESUMO

OBJECTIVE: Prokineticins are potent angiogenic hormones that use 2 receptors, prokineticin receptor-1 (PKR1) and PKR2, with important therapeutic use in anticancer therapy. Observations of cardiac and renal toxicity in cancer patients treated with antiangiogenic compounds led us to explore how PKR1 signaling functioned in heart and kidney in vivo. METHODS AND RESULTS: We generated mice with a conditional disruption of the PKR1 gene. We observed that PKR1 loss led to cardiomegaly, severe interstitial fibrosis, and cardiac dysfunction under stress conditions, accompanied by renal tubular dilation, reduced glomerular capillaries, urinary phosphate excretion, and proteinuria at later ages. Abnormal mitochondria and increased apoptosis were evident in both organs. Perturbation of capillary angiogenesis in both organs was restored at the adult stage potentially via upregulation of hypoxia-inducible factor-1 and proangiogenic factors. Compensatory mechanism could not revoke the epicardial and glomerular capillary networks, because of increased apoptosis and reduced progenitor cell numbers, consistent with an endogenous role of PKR1 signaling in stimulating epicardin+ progenitor cell proliferation and differentiation. CONCLUSIONS: Here, we showed for the first time that the loss of PKR1 causes renal and cardiac structural and functional changes because of deficits in survival signaling, mitochondrial, and progenitor cell functions in found both organs.


Assuntos
Inativação Gênica , Cardiopatias/genética , Nefropatias/genética , Rim/metabolismo , Miocárdio/metabolismo , Receptores Acoplados a Proteínas G/genética , Envelhecimento , Animais , Apoptose , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Predisposição Genética para Doença , Cardiopatias/metabolismo , Cardiopatias/patologia , Cardiopatias/fisiopatologia , Rim/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Nefropatias/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/patologia , Miocárdio/patologia , Neovascularização Fisiológica , Fenótipo , Receptores Acoplados a Proteínas G/metabolismo , Transdução de Sinais , Células-Tronco/metabolismo , Células-Tronco/patologia , Função Ventricular Esquerda
3.
Nephron Physiol ; 122(1-2): 1-6, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23434854

RESUMO

BACKGROUND/AIMS: Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. METHODS: We investigated 25 patients from 16 families with unexplained nephrocalcinosis and characteristic dental defects (amelogenesis imperfecta, gingival hyperplasia, impaired tooth eruption). To identify the causative gene, we performed genome-wide linkage analysis, exome capture, next-generation sequencing, and Sanger sequencing. RESULTS: All patients had bi-allelic FAM20A mutations segregating with the disease; 20 different mutations were identified. CONCLUSIONS: This autosomal recessive disorder, also known as enamel renal syndrome, of FAM20A causes nephrocalcinosis and amelogenesis imperfecta. We speculate that all individuals with biallelic FAM20A mutations will eventually show nephrocalcinosis.


Assuntos
Amelogênese Imperfeita/genética , Proteínas do Esmalte Dentário/genética , Predisposição Genética para Doença/genética , Mutação , Nefrocalcinose/genética , Adolescente , Adulto , Amelogênese Imperfeita/complicações , Amelogênese Imperfeita/patologia , Criança , Consanguinidade , Exoma/genética , Saúde da Família , Feminino , Genes Recessivos/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Nefrocalcinose/complicações , Nefrocalcinose/patologia , Linhagem , Análise de Sequência de DNA/métodos , Síndrome , Adulto Jovem
5.
Orphanet J Rare Dis ; 8: 9, 2013 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-23311583

RESUMO

BACKGROUND: Cockayne Syndrome CS (Type A - CSA; or CS Type I OMIM #216400) (Type B - CSB; or CS Type II OMIM #133540) is a rare autosomal recessive neurological disease caused by defects in DNA repair characterized by progressive cachectic dwarfism, progressive intellectual disability with cerebral leukodystrophy, microcephaly, progressive pigmentary retinopathy, sensorineural deafness photosensitivity and possibly orofacial and dental anomalies. METHODS: We studied the cranio-oro-facial status of a group of 17 CS patients from 15 families participating in the National Hospital Program for Clinical Research (PHRC) 2005 « Clinical and molecular study of Cockayne syndrome ¼. All patients were examined by two investigators using the Diagnosing Dental Defects Database (D[4]/phenodent) record form. RESULTS: Various oro-facial and dental anomalies were found: retrognathia; micrognathia; high- arched narrow palate; tooth crowding; hypodontia (missing permanent lateral incisor, second premolars or molars), screwdriver shaped incisors, microdontia, radiculomegaly, and enamel hypoplasia. Eruption was usually normal. Dental caries was associated with enamel defects, a high sugar/carbohydrate soft food diet, poor oral hygiene and dry mouth. Cephalometric analysis revealed mid-face hypoplasia, a small retroposed mandible and hypo-development of the skull. CONCLUSION: CS patients may have associated oro-dental features, some of which may be more frequent in CS children - some of them being described for the first time in this paper (agenesis of second permanent molars and radiculomegaly). The high susceptibility to rampant caries is related to a combination of factors as well as enamel developmental defects. Specific attention to these anomalies may contribute to diagnosis and help plan management.


Assuntos
Síndrome de Cockayne/patologia , Anormalidades Craniofaciais/patologia , Anormalidades Dentárias/patologia , Adolescente , Adulto , Cefalometria , Criança , Pré-Escolar , Síndrome de Cockayne/diagnóstico , Síndrome de Cockayne/genética , Anormalidades Craniofaciais/diagnóstico , Anormalidades Craniofaciais/genética , DNA Helicases/genética , Enzimas Reparadoras do DNA/genética , Face/anormalidades , Face/patologia , Feminino , Humanos , Lactente , Masculino , Fenótipo , Proteínas de Ligação a Poli-ADP-Ribose , Anormalidades Dentárias/diagnóstico , Anormalidades Dentárias/genética , Fatores de Transcrição/genética , Adulto Jovem
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