RESUMO
BACKGROUND: X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets and autosomal recessive hypophosphatemic rickets make up a group of renal phosphate wasting disorders with common clinical and biochemical characteristics. These three types of rickets are related to mutations in PHEX, FGF23 and dentin matrix protein 1 (DMP1), respectively. OBJECTIVE: The objective of the study was to evaluate the frequency of mutations that occur in these three genes associated with hypophosphatemic rickets. PATIENTS AND METHODS: In this study, we sequenced these genes in 76 members of 46 kindreds from a large hypophosphatemic rickets cohort. RESULTS: Forty-two individuals from 27 kindreds were found to have mutations in PHEX; 16 of which were novel. One subject had an FGF23 mutation. No individuals were found to have mutations in DMP1 consistent with the presence of recessive hypophosphatemic rickets. CONCLUSIONS: Our data highlight the wide spectrum of genetic variation that can be seen in PHEX, FGF23 and DMP1 when screening a large cohort with hypophosphatemic rickets.
Assuntos
Proteínas da Matriz Extracelular/genética , Raquitismo Hipofosfatêmico Familiar/genética , Fatores de Crescimento de Fibroblastos/genética , Doenças Genéticas Ligadas ao Cromossomo X , Mutação , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Fosfoproteínas/genética , Estudos de Coortes , Análise Mutacional de DNA , Raquitismo Hipofosfatêmico Familiar/diagnóstico , Saúde da Família , Feminino , Fator de Crescimento de Fibroblastos 23 , Testes Genéticos , Humanos , Masculino , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Neural tube defects (NTDs) occur in as many as 0.5-2 per 1000 live births in the United States. One of the most common and severe neural tube defects is meningomyelocele (MM) resulting from failed closure of the caudal end of the neural tube. MM has been induced by retinoic acid teratogenicity in rodent models. We hypothesized that genetic variants influencing retinoic acid (RA) induction via retinoic acid receptors (RARs) may be associated with risk for MM. METHODS: We analyzed 47 single nucleotide polymorphisms (SNPs) that span across the three retinoic acid receptor genes using the SNPlex genotyping platform. Our cohort consisted of 610 MM families. RESULTS: One variant in the RARA gene (rs12051734), three variants in the RARB gene (rs6799734, rs12630816, rs17016462), and a single variant in the RARG gene (rs3741434) were found to be statistically significant at p < 0.05. CONCLUSION: RAR genes were associated with risk for MM. For all associated SNPs, the rare allele conferred a protective effect for MM susceptibility.
Assuntos
Meningomielocele/genética , Polimorfismo de Nucleotídeo Único/genética , Receptores do Ácido Retinoico/genética , Alelos , Feminino , Frequência do Gene , Estudos de Associação Genética , Genótipo , Hispânico ou Latino/genética , Humanos , Masculino , Meningomielocele/etnologia , Defeitos do Tubo Neural/genética , Receptor alfa de Ácido Retinoico , População Branca/genética , Receptor gama de Ácido RetinoicoRESUMO
BACKGROUND: Meningomyelocele (MM) is a common human birth defect. MM is a disorder of neural development caused by contributions from genes and environmental factors that result in the NTD and lead to a spectrum of physical and neurocognitive phenotypes. METHODS: A multidisciplinary approach has been taken to develop a comprehensive understanding of MM through collaborative efforts from investigators specializing in genetics, development, brain imaging, and neurocognitive outcome. Patients have been recruited from five different sites: Houston and the Texas-Mexico border area; Toronto, Canada; Los Angeles, California; and Lexington, Kentucky. Genetic risk factors for MM have been assessed by genotyping and association testing using the transmission disequilibrium test. RESULTS: A total of 509 affected child/parent trios and 309 affected child/parent duos have been enrolled to date for genetic association studies. Subsets of the patients have also been enrolled for studies assessing development, brain imaging, and neurocognitive outcomes. The study recruited two major ethnic groups, with 45.9% Hispanics of Mexican descent and 36.2% North American Caucasians of European descent. The remaining patients are African-American, South and Central American, Native American, and Asian. Studies of this group of patients have already discovered distinct corpus callosum morphology and neurocognitive deficits that associate with MM. We have identified maternal MTHFR 667T allele as a risk factor for MM. In addition, we also found that several genes for glucose transport and metabolism are potential risk factors for MM. CONCLUSIONS: The enrolled patient population provides a valuable resource for elucidating the disease characteristics and mechanisms for MM development.