HNF1α mutations are present in half of clinically defined MODY patients in South-Brazilian individuals

Abstract

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset, and pancreatic beta cell dysfunction. Heterozygous mutations in at least seven genes can cause MODY. In the present study we investigated the relative prevalence of GCK (glucokinase) and HNF1α (hepatocyte nuclear factor 1α) mutations, the more frequent causes of MODY, in 13 South-Brazilian families with multiple cases of diabetes consistent with MODY. Heterozygous variants in GCK and HNF1α genes were observed respectively in one (7.7%), and six (46.2%) families. The six HNF1α variants are likely to cause diabetes in the families where they were observed. However, we could not ascertain whether the GCK Gly117Ser variant found in one family is a causal mutation.In conclusion, we have confi rmed in a South-Brazilian population that HNF1α mutations are a common cause of monogenic diabetes in adults selected with strict clinical diagnostic criteria. RESUMO Mutações HNF1α Estão Presentes na Metade dos Pacientes da Região Sul do Brasil Clinicamente Diagnosticados com MODY.O maturity-onset diabetes of the young (MODY) é uma forma monogênica de diabetes melito caracterizada por herança autossômica dominante, de instalação precoce, como disfunção da célula beta pancreática. Mutações heterozigotas em pelo menos sete genes causam MODY. No presente estudo, investigamos a prevalência relativa das mutações da GCK (glucokinase) e HNF1α (hepatocyte nuclear factor 1α), as causas mais freqüentes de MODY, em 13 famílias sul-brasileiras com múltiplos casos de diabetes consistentes com MODY. Variantes heterozigotas nos genes da GCK e HNF1α foram observadas, respectivamente, em uma (7,7%) e em seis (46,2%) famílias. As seis variantes do HNF1α provavelmente causaram o diabetes nas famílias nas quais foram observadas. No entanto, não se pode afi rmar que a variante GCK Gly117Ser encontrada em uma família seja a mutação causal. Em conclusão, confi rmamos que, em uma população do sul do Brasil, as mutações HNF1α são uma causa comum de diabetes monogênico em adultos selecionados com critérios clínicos diagnósticos estritos.

Incidental mild hyperglycemia in children: two MODY 2 families identified in Brazilian subjects

“…p.Glu221Lys mutation was associated with MODY 2 in Italian subjects (30). Even though they have already been reported in other ethnicities, these GCK mutations have never been identified in Brazilian families (12)(13)(14).…”

“…In publications including only Brazilian families, a total of five GCK variants have been previously described (12)(13)(14): two were novel mutations (14), one was a glucokinase polymorphism (intronic variant that did not co-segregate with diabetes) (12), and another variant that could not be ascertained as a causal mutation (it was not present in a family member with diabetes) (13). This data could not cover all GCK mutations found in Brazilian subjects, as some may have not been published yet, or may be only available in annals of scientific meetings.…”

“…Among identified mutations, MODY 3 was the most common type, followed by MODY 2 (only few reported variants). MODY 2 and 3 mutations did not explain the majority of MODY cases in the Brazilian population, which resulted in a high prevalence of MODY X (no known mutation), ranging from 46.2 to 73.9% of the suspected cases (12)(13)(14).…”

Variants of the HNF1α gene: a molecular approach concerning diabetic patients from southern Brazil

“…In Brazil, the prevalence of MODY3 is 13%–46.2%, followed by MODY2 with 7.7%–12.5% (Moises et al , 2001; Furuzawa et al , 2008). Furthermore, Maraschin et al (2008) suggested that the majority MODY cases in Brazil are due to MODY-X genes. These MODY subtypes are rare disorders identified in some families, while the locus involved (called MODY-X) has not yet elucidated (Maraschin et al , 2008).…”

Utilização de Análise Bioinformática e Validação por PCR Quantitativa em Tempo Real na Identificação da Indução Transcricional dos Fatores de Transcrição E2F1 e E2F4 em Linhagens de Glioblastoma.

“…Discussão O HNF1, também conhecido por HNF1A (Hepatocyte Nuclear Factor 1 -Alpha) e TCF-1 (Transcription Factor 1) codifica um FT requerido para a expressão de diversos genes específicos do fígado. Esse gene tem sido relacionado a doenças (segundo uma extensa literatura) como diabetes, incluindo diabetes mellitus tipo I e II, diabetes gestacional e (Harries et al, 2006;Narayana et al, 2006;Rowley et al, 2006;Maraschin et al, 2008;Umeyama et al, 2009;Pal et al, 2010;Pinés Corrales et al, 2010), doenças renais (Malecki et al, 2005), adenoma (Bluteau et al, 2002;Laurent-Puig et al, 2003), câncer de mama, de endométrio e de ovário (Rebouissou et al, 2004), neoplasias colorretais (Jeannot et al, 2006;Bélanger et al, 2010) e neoplasias de esôfago (Piessen et al, 2007).…”