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New HNF-1α nonsense mutation causes maturity-onset diabetes of the young type 3.

Nogaroto V, Svidnicki PV, Bonatto N, Milléo FQ, Almeida MC, Vicari MR, Artoni RF - Clinics (Sao Paulo) (2011)

View Article: PubMed Central - PubMed

Affiliation: Departamento de Biologia Estrutural, Molecular e Genética, Universidade Estadual de Ponta Grossa, Ponta Grossa, Paraná, Brazil. vivianenogaroto@hotmail.com

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Epidemiological studies indicate that approximately 5% of people previously classified as type 2 diabetes mellitus carriers and 10% of those considered as type 1 are, in fact, carriers of maturity‐onset diabetes of the young (MODY), a subtype of non‐insulin‐dependent diabetes mellitus... The diabetic phenotype of the carriers of this mutation is due to altered gene expression of pancreatic β‐cells, mainly of the genes encoding insulin, the glucose transporter Glut2, amino acid transporters and some mitochondrial enzymes., The identification of the MODY genes has important clinical implications for patients, and their correct diagnosis is essential for a more appropriate treatment of the disease... Because MODY 3 is the most commonly occurring form of the disease in Brazil, oligonucleotides were synthesized for the flanking regions (introns) of the 10 exons of HNF‐1α... More than 120 mutations have already been identified in the HNF1‐α gene, e.g. missense, nonsense, frameshift and splice‐site MODY mutations, in all exons analyzed... Furthermore, the age at diagnosis of diabetes varies according to the type of the HNF‐1α mutations: the median age at diagnosis was lower in patients with truncating mutations than in those with missense mutations... Functionally, the HNF‐1α protein can be divided in three regions: amino‐terminal dimerization domain (amino acids 1–32), homeodomain binding domain (203–276) and transactivation carboxyl‐terminal domain (281–631)... The mutations in this protein are more frequent in the homeodomain regions and in a near amino‐terminal region, between residues 91 and 185,, in agreement with our findings (mutation at amino acid 113)... This region is responsible for binding and specificity in the interaction with DNA., Studies indicated that suppression of HNF‐1α function affects β‐cell metabolism leading to MODY 3 and concluded that normal function of the HNF‐1α protein is required for correct transcription of the insulin gene... In conclusion, the data presented in this study describe a new mutation for MODY type 3 and suggest functional significance of this genetic alteration in the insulin secretion process, besides highlighting the diagnostic importance of this type of diabetes aiming the control and clinical follow up... This study was financed by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), Fundação Araucária (Fundação Araucária de Apoio ao Desenvolvimento Científico e Tecnológico do Estado do Paraná) and, SETI/UGF (Secretaria de Estado da Ciência, Tecnologia e Ensino Superior/Unidade Gestora do Fundo do Paraná).

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Heredogram representing three generations (Ι, ΙΙ and ΙΙΙ) of the family analyzed in this study. The arrow indicates the proband and the asterisks (*) represent the members examined in this work.
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f1-cln_66p167: Heredogram representing three generations (Ι, ΙΙ and ΙΙΙ) of the family analyzed in this study. The arrow indicates the proband and the asterisks (*) represent the members examined in this work.

Mentions: After nucleotide alignment, the presence of a mutation in exon 2 of the HNF1‐α gene was detected in some members of the family: the proband and her daughters (Figure 1). The transition of a guanine to an adenine nucleotide at position 339 of codon 113 (TGG→TGA) has generated a nonsense mutation in this position (W113X), not yet described in the literature, which inhibits the formation of a functional protein in the affected individuals. More than 120 mutations have already been identified in the HNF1‐α gene, e.g. missense, nonsense, frameshift and splice‐site MODY mutations, in all exons analyzed.11 The majority of mutations in the HNF‐1α protein lead to the formation of nonfunctional heterodimers with the product of the normal HNF‐1α allele, preventing them from binding to DNA.


New HNF-1α nonsense mutation causes maturity-onset diabetes of the young type 3.

Nogaroto V, Svidnicki PV, Bonatto N, Milléo FQ, Almeida MC, Vicari MR, Artoni RF - Clinics (Sao Paulo) (2011)

Heredogram representing three generations (Ι, ΙΙ and ΙΙΙ) of the family analyzed in this study. The arrow indicates the proband and the asterisks (*) represent the members examined in this work.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3044575&req=5

f1-cln_66p167: Heredogram representing three generations (Ι, ΙΙ and ΙΙΙ) of the family analyzed in this study. The arrow indicates the proband and the asterisks (*) represent the members examined in this work.
Mentions: After nucleotide alignment, the presence of a mutation in exon 2 of the HNF1‐α gene was detected in some members of the family: the proband and her daughters (Figure 1). The transition of a guanine to an adenine nucleotide at position 339 of codon 113 (TGG→TGA) has generated a nonsense mutation in this position (W113X), not yet described in the literature, which inhibits the formation of a functional protein in the affected individuals. More than 120 mutations have already been identified in the HNF1‐α gene, e.g. missense, nonsense, frameshift and splice‐site MODY mutations, in all exons analyzed.11 The majority of mutations in the HNF‐1α protein lead to the formation of nonfunctional heterodimers with the product of the normal HNF‐1α allele, preventing them from binding to DNA.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Biologia Estrutural, Molecular e Genética, Universidade Estadual de Ponta Grossa, Ponta Grossa, Paraná, Brazil. vivianenogaroto@hotmail.com

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Epidemiological studies indicate that approximately 5% of people previously classified as type 2 diabetes mellitus carriers and 10% of those considered as type 1 are, in fact, carriers of maturity‐onset diabetes of the young (MODY), a subtype of non‐insulin‐dependent diabetes mellitus... The diabetic phenotype of the carriers of this mutation is due to altered gene expression of pancreatic β‐cells, mainly of the genes encoding insulin, the glucose transporter Glut2, amino acid transporters and some mitochondrial enzymes., The identification of the MODY genes has important clinical implications for patients, and their correct diagnosis is essential for a more appropriate treatment of the disease... Because MODY 3 is the most commonly occurring form of the disease in Brazil, oligonucleotides were synthesized for the flanking regions (introns) of the 10 exons of HNF‐1α... More than 120 mutations have already been identified in the HNF1‐α gene, e.g. missense, nonsense, frameshift and splice‐site MODY mutations, in all exons analyzed... Furthermore, the age at diagnosis of diabetes varies according to the type of the HNF‐1α mutations: the median age at diagnosis was lower in patients with truncating mutations than in those with missense mutations... Functionally, the HNF‐1α protein can be divided in three regions: amino‐terminal dimerization domain (amino acids 1–32), homeodomain binding domain (203–276) and transactivation carboxyl‐terminal domain (281–631)... The mutations in this protein are more frequent in the homeodomain regions and in a near amino‐terminal region, between residues 91 and 185,, in agreement with our findings (mutation at amino acid 113)... This region is responsible for binding and specificity in the interaction with DNA., Studies indicated that suppression of HNF‐1α function affects β‐cell metabolism leading to MODY 3 and concluded that normal function of the HNF‐1α protein is required for correct transcription of the insulin gene... In conclusion, the data presented in this study describe a new mutation for MODY type 3 and suggest functional significance of this genetic alteration in the insulin secretion process, besides highlighting the diagnostic importance of this type of diabetes aiming the control and clinical follow up... This study was financed by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), Fundação Araucária (Fundação Araucária de Apoio ao Desenvolvimento Científico e Tecnológico do Estado do Paraná) and, SETI/UGF (Secretaria de Estado da Ciência, Tecnologia e Ensino Superior/Unidade Gestora do Fundo do Paraná).

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