Clinical follow-up of two Brazilian subjects with glucokinase-MODY (MODY2) with description of a novel mutation

Della-Manna, T.; Silva, Magnus R. da; Chacra, Antônio Roberto; Kunii, Ilda S.; Rolim, Ana Luiza; Furuzawa, Gilberto K.; Maciel, Rui M. B.; Reis, André

doi:10.1590/s0004-27302012000800005

Cited by 10 publications

(8 citation statements)

References 41 publications

(41 reference statements)

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“…В 2012 г. T. Della Manna и соавт. [6] отметили, что распространенность в Бразилии MODY варьировала от 0,3% до 2,4% случаев диабета, из них примерно 70% случаев приходится на MODY3 и MODY2. Относительная распространенность подтипов MODY различается.…”

Section: Introductionunclassified

MODY2 diagnostic issues in adults

et al. 2019

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Approximately 90% of all cases of diabetes mellitus in adults involve type 2 diabetes, while the prevalence of maturity-onset diabetes of the young (MODY) remains undetermined leading to inappropriate treatment regimens. One of the most common monogenic forms of diabetes is a disease caused by a mutation in the glucokinase gene, MODY2. Knowledge of the clinical features of the disease allows the selection of patients with a high risk of mutation in the glucokinase gene and verification of diagnosis for molecular genetic research. This paper reflects the clinical features of MODY2 and the difficulties of diagnosis in adults. Furthermore, it presents a clinical case of a patient with MODY2 demonstrating all the features of this type of diabetes. A family member with a mutation in the gene allows to predict the nature of carbohydrate metabolism disorders in first degree relatives. A targeted study of only one part of the glucokinase gene in molecular genetic research is sufficient to confirm the diagnosis in relatives.

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Section: Introductionunclassified

MODY2 diagnostic issues in adults

et al. 2019

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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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“…To date, eleven forms of MODY, distinguishable by genetic, metabolic, and clinical heterogeneity, have been described. Through molecular genetic studies of diabetes, mutations related to this disorder have been identified in HNF4A , GCK , HNF1A , PDX1 , HNF1B , NEUROD1 , KLF11 , CEL , PAX4 , INS , and BLK, which are associated with MODY 1 to 11, respectively 7. Of the various forms of the disease, MODY 2/Glucokinase and MODY3 are the most frequent, and their prevalence varies between countries.…”

Section: Introductionmentioning

confidence: 99%

Evolution- and Structure-Based Computational Strategy Reveals the Impact of Deleterious Missense Mutations on MODY 2 (Maturity-Onset Diabetes of the Young, Type 2)

George¹,

Chakraborty²,

Haneef³

et al. 2014

Theranostics

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Heterozygous mutations in the central glycolytic enzyme glucokinase (GCK) can result in an autosomal dominant inherited disease, namely maturity-onset diabetes of the young, type 2 (MODY 2). MODY 2 is characterised by early onset: it usually appears before 25 years of age and presents as a mild form of hyperglycaemia. In recent years, the number of known GCK mutations has markedly increased. As a result, interpreting which mutations cause a disease or confer susceptibility to a disease and characterising these deleterious mutations can be a difficult task in large-scale analyses and may be impossible when using a structural perspective. The laborious and time-consuming nature of the experimental analysis led us to attempt to develop a cost-effective computational pipeline for diabetic research that is based on the fundamentals of protein biophysics and that facilitates our understanding of the relationship between phenotypic effects and evolutionary processes. In this study, we investigate missense mutations in the GCK gene by using a wide array of evolution- and structure-based computational methods, such as SIFT, PolyPhen2, PhD-SNP, SNAP, SNPs&GO, fathmm, and Align GVGD. Based on the computational prediction scores obtained using these methods, three mutations, namely E70K, A188T, and W257R, were identified as highly deleterious on the basis of their effects on protein structure and function. Using the evolutionary conservation predictors Consurf and Scorecons, we further demonstrated that most of the predicted deleterious mutations, including E70K, A188T, and W257R, occur in highly conserved regions of GCK. The effects of the mutations on protein stability were computed using PoPMusic 2.1, I-mutant 3.0, and Dmutant. We also conducted molecular dynamics (MD) simulation analysis through in silico modelling to investigate the conformational differences between the native and the mutant proteins and found that the identified deleterious mutations alter the stability, flexibility, and solvent-accessible surface area of the protein. Furthermore, the functional role of each SNP in GCK was identified and characterised using SNPeffect 4.0, F-SNP, and FASTSNP. We hope that the observed results aid in the identification of disease-associated mutations that affect protein structure and function. Our in silico findings provide a new perspective on the role of GCK mutations in MODY2 from an evolution-based structure-centric point of view. The computational architecture described in this paper can be used to predict the most appropriate disease phenotypes for large-genome sequencing projects and to provide individualised drug therapy for complex diseases such as diabetes.

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Clinical follow-up of two Brazilian subjects with glucokinase-MODY (MODY2) with description of a novel mutation

Cited by 10 publications

References 41 publications

MODY2 diagnostic issues in adults

MODY2 diagnostic issues in adults

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

Evolution- and Structure-Based Computational Strategy Reveals the Impact of Deleterious Missense Mutations on MODY 2 (Maturity-Onset Diabetes of the Young, Type 2)

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