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Mutations in HNF1A Gene are not a Common Cause of Familial Young-Onset Diabetes in Iran.

ABSTRACT: Mutations in hepatocyte nuclear factor-1 alpha (HNF1A) as a homeodomain transcription factor which regulates variety of genes, are the most common cause of maturity-onset diabetes of the young (MODY). Detection of HNF1A mutations not only classifies the subtype, but also predicts the likely clinical course and may alters the method of treatment from insulin to the oral sulphonylureas, which is shown to improve glycemic control. The coding and promoter regions of HNF1A gene were screened for mutations in 34 unrelated Iranian MODY patients. We identified one novel missense mutation (C49G) and two novel polymorphisms and 8 recently identified SNPs in the HNF1A gene. It is possible that in Iran, other yet to be identified genes are responsible for the familial young onset diabetes. Hence, there is a need for more extensive genetic analyses in Iranian patients with familial young onset diabetes.

SUBMITTER: Moghbeli M

PROVIDER: S-EPMC5766466 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Mutations in HNF1A Gene are not a Common Cause of Familial Young-Onset Diabetes in Iran.

Moghbeli Meysam M Naghibzadeh Bahram B Ghahraman Martha M Fatemi Sedigheh S Taghavi Morteza M Vakili Rahim R Abbaszadegan Mohammad Reza MR

Indian journal of clinical biochemistry : IJCB 20170413 1

Mutations in hepatocyte nuclear factor-1 alpha (HNF1A) as a homeodomain transcription factor which regulates variety of genes, are the most common cause of maturity-onset diabetes of the young (MODY). Detection of HNF1A mutations not only classifies the subtype, but also predicts the likely clinical course and may alters the method of treatment from insulin to the oral sulphonylureas, which is shown to improve glycemic control. The coding and promoter regions of <i>HNF1A</i> gene were screened f ...[more]

PMID: 29371776

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Project description:ObjectiveInactivating heterozygous mutations in the GCK gene are a common cause of MODY and result in mild fasting hyperglycaemia, which does not require treatment. We aimed to identify the frequency, clinical and molecular features of GCK mutations in a Turkish paediatric cohort.Design and patientsFifty-four unrelated probands were selected based on the following criteria: age of diagnosis ≤17 years, family history of diabetes in at least two generations, anti-GAD/ICA negative, BMI<95.p and follow-up with diet, oral antidiabetic drug or low-dose insulin treatment (≤0·5U/kg/d). A MODY probability score (www.diabetesgenes.org) was calculated and 21 patients with a score ≥75%, HbA1c levels ≤7·5% (58·5 mmol/mol) and fasting blood glucose (FBG) levels 99-145 mg/dl (5·5-8·0 mmol/l) were selected for Sanger sequencing of the GCK gene. Targeted next-generation sequencing for all known monogenic diabetes genes was undertaken for any patient without a GCK gene mutation.ResultsGCK gene mutations (pathogenic or likely pathogenic variants) and a novel intronic variant of uncertain significance (c.208 + 3A>T) were identified in 13/54 probands (24%). Twelve of these patients had a MODY probability score ≥75%. FBG level and 2-h glucose level in OGTT were 123 ± 14 mg/dl (6·8 ± 0·7 mmol/l) (107-157 mg/dl) and 181 ± 30 mg/dl (10·1 ± 1·6 mmol/l) (136-247 mg/dl), respectively. Average of glucose increment in OGTT was 58 ± 27 mg/dl (3·2 ± 1·5 mmol/l) (19-120 mg/dl), and mean HbA1c level was 6·5 ± 0·5% (47·5 ± 5·5 mmol/mol) (5·9-7·6%). Five novel missense mutations were identified (p.F123S, p.L58P, p.G246A, p.F419C, and p.S151C). Two patients treated with low-dose insulin before the molecular analysis were able to stop treatment.ConclusionsApproximately 1 in 4 MODY cases in this Turkish paediatric cohort have a GCK mutation. Selection of patients for GCK gene analysis using the MODY probability score was an effective way of identifying most (11/12) patients with a GCK mutation.

Dataset Information

Mutations in HNF1A Gene are not a Common Cause of Familial Young-Onset Diabetes in Iran.

Publications

Mutations in HNF1A Gene are not a Common Cause of Familial Young-Onset Diabetes in Iran.

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