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

Bonatto, Naieli; Nogaroto, Viviane; Svidnicki, Paulo Vinícius; Milléo, Fábio Quirillo; Grassiolli, Sabrina; Almeida, Mara Cristina de; Vicari, Marcelo Ricardo; Artoni, Roberto Ferreira

doi:10.1590/s1415-47572012005000061

Cited by 9 publications

(11 citation statements)

References 27 publications

(36 reference statements)

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“…The genetic characterization and clinical parameters of these patients have been described previously [38]. …”

Section: Methodsmentioning

confidence: 99%

Low Frequencies of Autoimmunity-Associated PTPN22 Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Heneberg¹,

Malá²,

Yorifuji³

et al. 2015

Int Arch Allergy Immunol

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Background: The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes lymphoid tyrosine phosphatase (LYP), which is expressed primarily in lymphoid tissues. The functional but geographically highly variable PTPN22 single-nucleotide polymorphisms (SNPs), particularly c.1858C>T, contribute to the onset and progression of autoimmunity-associated diseases and facilitate the expression of disease-associated autoantibodies. In Central Europe, 17-25% of patients with monogenic diabetes (maturity-onset diabetes of the young, MODY) transiently express islet cell autoantibodies. Methods: We addressed the links between the functional and geographically variable PTPN22 SNPs with MODY manifestation and the expression of islet cell autoantibodies in 276 MODY patients who originated from four regions (the Czech Republic, Israel, Japan and Brazil). Results: The frequency of PTPN22 polymorphisms in the MODY patients was similar to those in geographically matched healthy populations, with the exception of c.788G>A, the minor allele frequency of which was significantly elevated in the Czech hepatocyte nuclear factor 1-α (HNF1A) MODY patients [odds ratio (OR) 4.8, 95% confidence interval (CI) 2.2-10.7] and the Brazilian MODY patients (OR 8.4, 95% CI 1.8-39.1). A barely significant increase in the c.788G>A minor allele was also detected in the islet cell autoantibody-positive Czech MODY patients. However, c.788A behaves as a loss-of-function mutant in T cells, and thus protects against autoimmunity. Conclusions: MODY patients (including islet cell autoantibody-positive cases) do not display any increase in autoimmunity-associated PTPN22 alleles. The absence of autoimmunity-associated PTPN22 alleles was also demonstrated in latent autoimmune diabetes in adults, which suggests that the slow kinetics of the onset of autoantibodies is subject to a regulation that is different from that experienced in type 1 diabetes and other autoimmune disorders.

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“…The genetic characterization and clinical parameters of these patients have been described previously [38]. …”

Section: Methodsmentioning

confidence: 99%

Low Frequencies of Autoimmunity-Associated PTPN22 Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Heneberg¹,

Malá²,

Yorifuji³

et al. 2015

Int Arch Allergy Immunol

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“…; Bonatto et al. ). Characteristics of MODY carriers are: (1) Early age of diabetes onset, (2) overweight or obesity are rarely associated, (3) the levels of insulin are usually within the normal range, though inappropriately low for the degree of hyperglycemia, (4) family history of diabetes in at least three generations, showing an autosomal dominant mode of inheritance, and (5) show non‐insulin dependence (Klupa et al.…”

Section: Introductionmentioning

confidence: 97%

“…Mutations in the HNF1A gene (OMIM 142410) are the most common cause of MODY (Shields et al 2010). Furthermore, three frequent polymorphisms (I27L, A98V, and S487N) have been described in patients with T2D (Holmkvist et al 2006;Giuffrida et al 2009;Bonatto et al 2012). Characteristics of MODY carriers are:…”

Section: Introductionmentioning

confidence: 99%

Identification and functional analysis of c.422_423InsT, a novel mutation of the HNF1A gene in a patient with diabetes

Magaña-Cerino

Luna-Arias

Labra-Barrios

et al. 2016

Molec Gen & Gen Med

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Background HNF1A gene regulates liver‐specific genes, and genes that have a role in glucose metabolism, transport, and secretion of insulin. HNF1A gene mutations are frequently associated with type 2 diabetes. HNF1A protein has three domains: the dimerization domain, the DNA‐binding domain, and the trans‐activation domain. Some mutations in the dimerization or DNA‐binding domains have no influence on the normal allele, while others have dominant negative effects. The I27L, A98V, and S487N polymorphisms are common variants of the HNF1A gene; they have been found in T2D and non‐diabetic subjects.Methods and ResultsWe searched for mutations in the first three exons of the HNF1A gen in an Amerindian population of 71 diabetic patients. DNA sequencing revealed the previously reported I27L polymorphism (c.79A>C) in 53% of diabetic patients and in 67% of the control group. Thus, the I27L/L27L polymorphism might be a marker of Amerindians. In addition, we found the c.422_423InsT mutation in the HNF1A gene of one patient, which had not been previously reported. This mutation resulted in a frame shift of the open reading frame and a new translation stop in codon 187, leading to a truncated polypeptide of 186 amino acids (Q141Hfs*47). This novel mutation affects the DNA‐binding capacity of the mutant HNF1A protein by EMSA; its intracellular localization by fluorescence and confocal microscopy, and a dominant‐negative effect affecting the DNA‐binding capacity of the normal HNF1A by EMSA. We also studied the homology modeling structure to understand the effect of this mutation on its DNA‐binding capacity and its dominant negative effect.ConclusionThe HNF1A Q141Hfs*47 mutant polypeptide has no DNA‐binding capacity and exerts a dominant negative effect on the HNF1A protein. Therefore, it might produce severe phenotypic effects on the expression levels of a set of β‐cell genes. Consequently, its screening should be included in the genetic analysis of diabetic patients after more functional studies are performed.

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“…These data allow us to estimate the number of MODY cases in Brazil as approximately 140 000 to 280 000. However, until 2016, around 200 subjects of about 50 Brazilian families diagnosed with the 2 most common subtypes of MODY ( GCK and HNF1A ) have been described . Hence, MODY cases are clearly underestimated in Brazil.…”

Section: Introductionmentioning

confidence: 99%

“…However, until 2016, around 200 subjects of about 50 Brazilian families diagnosed with the 2 most common subtypes of MODY (GCK and HNF1A) have been described. [5][6][7][8][9][10][11][12][13][14][15][16][17][18] Hence, MODY cases are clearly underestimated in Brazil. Besides that, there is a great racial diversity in Brazilian people, contributing to a wide genetic background, an important difference from countries with more homogeneous population.…”

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confidence: 99%

Clinical application of ACMG‐AMP guidelines in HNF1A and GCK variants in a cohort of MODY families

et al. 2017

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Maturity-onset diabetes of the young (MODY) is a form of monogenic diabetes with autosomal dominant inheritance. GCK -MODY and HNF1A -MODY are the prevalent subtypes. Currently, there is growing concern regarding the correct interpretation of molecular genetic findings. The American College of Medical Genetics and Genomics (ACMG) updated guidelines to interpret and classify molecular variants. This study aimed to determine the prevalence of MODY ( GCK / HNF1A ) in a large cohort of Brazilian families, to report variants related to phenotype, and to classify them according to ACMG guidelines. One hundred and nine probands were investigated, 45% with clinical suspicion of GCK -MODY and 55% with suspicion of HNF1A -MODY. Twenty-five different variants were identified in GCK gene (30 probands-61% of positivity), and 7 variants in HNF1A (10 probands-17% of positivity). Fourteen of them were novel (12- GCK /2- HNF1A ). ACMG guidelines were able to classify a large portion of variants as pathogenic (36%- GCK /86%- HNF1A ) and likely pathogenic (44%- GCK /14%- HNF1A ), with 16% (5/32) as uncertain significance. This allows us to determine the pathogenicity classification more efficiently, and also reinforces the suspected associations with the phenotype among novel variants.

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

Cited by 9 publications

References 27 publications

Low Frequencies of Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Low Frequencies of Autoimmunity-Associated <b><i>PTPN22</i></b> Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoantibodies

Identification and functional analysis of c.422_423InsT, a novel mutation of the HNF1A gene in a patient with diabetes

Clinical application of ACMG‐AMP guidelines in HNF1A and GCK variants in a cohort of MODY families

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