RESUMO
BACKGROUND: Genetic Hypophosphatemic Rickets (HR) is a group of diseases characterized by renal phosphate wasting with inappropriately low or normal 1,25-dihydroxyvitamin D3 (1,25(OH)2D) serum levels. The most common form of HR is X-linked dominant HR (XLHR) which is caused by inactivating mutations in the PHEX gene. The purpose of this study was to perform genetic diagnosis in a cohort of patients with clinical diagnosis of HR, to perform genotype-phenotype correlations of those patients and to compare our data with other HR cohort studies. METHODS: Forty three affected individuals from 36 non related families were analyzed. For the genetic analysis, the PHEX gene was sequenced in all of the patients and in 13 cases the study was complemented by mRNA sequencing and Multiple Ligation Probe Assay. For the genotype-phenotype correlation study, the clinical and biochemical phenotype of the patients was compared with the type of mutation, which was grouped into clearly deleterious or likely causative, using the Mann-Whitney and Fisher's exact test. RESULTS: Mutations in the PHEX gene were identified in all the patients thus confirming an XLHR. Thirty four different mutations were found distributed throughout the gene with higher density at the 3' end. The majority of the mutations were novel (69.4%), most of them resulted in a truncated PHEX protein (83.3%) and were family specific (88.9%). Tubular reabsorption of phosphate (TRP) and 1,25(OH)2D serum levels were significantly lower in patients carrying clearly deleterious mutations than in patients carrying likely causative ones (61.39 ± 19.76 vs. 80.14 ± 8.80%, p = 0.028 and 40.93 ± 30.73 vs. 78.46 ± 36.27 pg/ml, p = 0.013). CONCLUSIONS: PHEX gene mutations were found in all the HR cases analyzed, which was in contrast with other cohort studies. Patients with clearly deleterious PHEX mutations had lower TRP and 1,25(OH)2D levels suggesting that the PHEX type of mutation might predict the XLHR phenotype severity.
Assuntos
Calcitriol/sangue , Calcitriol/genética , Raquitismo Hipofosfatêmico Familiar/genética , Doenças Genéticas Ligadas ao Cromossomo X , Mutação , Endopeptidase Neutra Reguladora de Fosfato PHEX/genética , Fosfatos/sangue , Raquitismo/genética , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Análise Mutacional de DNA , Feminino , Genes Dominantes , Predisposição Genética para Doença , Genótipo , Humanos , Lactente , Túbulos Renais/metabolismo , Masculino , Fenótipo , Fosfatos/químicaAssuntos
Transformação Celular Neoplásica/genética , Inversão Cromossômica , Cromossomos Humanos Par 3 , Trombocitemia Essencial/complicações , Células da Medula Óssea/patologia , Progressão da Doença , Humanos , Cariotipagem , Leucemia Mieloide Aguda/genética , Masculino , Pessoa de Meia-Idade , Trombocitemia Essencial/patologiaAssuntos
Anemia Refratária com Excesso de Blastos/complicações , Anemia Refratária com Excesso de Blastos/genética , Cromossomos Humanos Par 21 , Cromossomos Humanos Par 8 , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteínas de Ligação a DNA/genética , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Translocação Genética , Idoso , Humanos , Hibridização In Situ , Cariotipagem , Masculino , Proteínas de Fusão Oncogênica/genética , Proteína 1 Parceira de Translocação de RUNX1RESUMO
Clear cell renal cell carcinoma (ccRCC) is the most common malignant neoplasm of the kidney. The majority of hereditary and sporadic ccRCC cases are associated with germline and somatic mutations in the Von Hippel-Lindau gene (VHL), respectively. Gross deletions at the VHL locus can result either in ccRCC or in a mild clinical phenotype, with the absence of ccRCC development. Our goal in this study was to identify the molecular basis responsible for these differences in the clinical behavior in order to predict patients' phenotype. Using multiplex ligation-dependent amplification (MLPA), we identified and characterized gross VHL deletions in Spanish VHL families. A candidate gene related to this clinical association, HSPC300, was identified and depleted by RNA interference. It was possible to narrow the susceptibility region related to the mild clinical phenotype down to approximately 14 kb that included HSPC300 (C3orf10), a regulator of actin dynamics and cytoskeleton organization. Whereas 9 out of 10 families with ccRCC retained HSPC300 in the germline, loss of the HSPC300 locus was associated with mild clinical presentation of the disease in 6 out of 8 families. In fact, genetic depletion of HSPC300 resulted in cytoskeleton abnormalities and cytokinesis arrest in several tumor cell lines including ccRCC cells, suggesting that tumor cell proliferation was compromised in the absence of HSPC300. These clinical and functional data indicate a relevant function of HSPC300 in tumor cell progression, and suggest future therapeutic strategies based upon the inhibition of HSPC300 in renal cell carcinoma and possibly on other cancers.
Assuntos
Actinas/metabolismo , Carcinoma de Células Renais/genética , Cromossomos Humanos Par 3/genética , Proteínas do Citoesqueleto/genética , Neoplasias Renais/genética , Doença de von Hippel-Lindau/genética , Adolescente , Adulto , Idoso , Carcinoma de Células Renais/patologia , Divisão Celular/genética , Linhagem Celular Tumoral , Citoesqueleto/genética , Citoesqueleto/patologia , Análise Mutacional de DNA , Feminino , Humanos , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Interferência de RNA , Deleção de Sequência , EspanhaRESUMO
In two patients with hematological neoplasias a tandem repetition of chromosome 21 in the bone marrow was revealed by cytogenetic analysis. The disease was different in the two patients: one was of the lymphoid type, acute lymphoblastic leukemia type L1, and the other was of the myeloid type, acute nonlymphoblastic leukemia type M2. In one case this chromosomal abnormality resulted in amplification of the AML1 gene (HUGO nomenclature: RUNX1), whereas in the other case the AML1 gene was not included in the tandem repetition, showing that apparently similar cytogenetic aberrations may be different at the molecular level.
