Assuntos
Técnicas de Laboratório Clínico , Patologia Clínica , Reação em Cadeia da Polimerase/normas , Sequência de Bases , Soluções Tampão , Primers do DNA , Genoma Humano , Humanos , Indicadores e Reagentes , Reação em Cadeia da Polimerase/métodos , Sensibilidade e Especificidade , Análise de Sequência de DNA , Taq PolimeraseRESUMO
Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of beta-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.
Assuntos
Proteínas de Ligação a DNA , Diabetes Mellitus Tipo 2/genética , Heterogeneidade Genética , Proteínas Nucleares , Adolescente , Adulto , Criança , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 5 , Cromossomos Humanos Par 6 , Feminino , Ligação Genética , Genótipo , Glucoquinase/genética , Fator 1 Nuclear de Hepatócito , Fator 1-alfa Nuclear de Hepatócito , Fator 1-beta Nuclear de Hepatócito , Humanos , Escore Lod , Masculino , Repetições de Microssatélites , Mutação , Linhagem , Fatores de Transcrição/genéticaRESUMO
The hepatocyte nuclear factor-1beta (HNF-1beta) transcription factor controls endoderm development. Human mutations cause early-onset diabetes mellitus and have recently been associated with dysplastic, hypoplastic, and glomerulocystic kidneys. A new kindred with this "renal cysts and diabetes" syndrome is described, and nephrogenic HNF-1beta expression is defined. The proband had congenital cystic kidneys: over the next 12 yr, his renal function was impaired, but he was normoglycemic. His mother developed diabetes during pregnancy: renal ultrasonography at age 24 yr was normal, but she subsequently developed cysts. Both subjects have a heterozygous frameshift mutation in HNF-1beta that results from a 1-bp insertion in exon 5 (Y352fsinsA). When reverse-transcription PCR and in situ hybridization were used, HNF-1beta mRNA was detected in normal human metanephroi, with the highest levels of transcripts localized to fetal medullary and cortical collecting ducts and low levels of expression in nephrogenic cortex mesenchyme, primitive nephron tubules, and immature glomeruli. These results constitute the first demonstration of HNF-1beta expression during human nephrogenesis and emphasize a disease spectrum associated with HNF-1beta mutation.