HNF1A gene p.I27L is associated with early-onset, maturity-onset diabetes of the young-like diabetes in Turkey

Beysel, Selvihan; Eyerci, Nilnur; Pınarlı, Ferda Alpaslan; Kızılgül, Muhammed; Ozcelik, Ozgur; Çalışkan, Mustafa; Çakal, Erman

doi:10.1186/s12902-019-0375-2

Cited by 13 publications

(10 citation statements)

References 32 publications

(56 reference statements)

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“…Therefore, we decided to search for independent gene mutations that could explain his impaired insulin secretion. Among the mutations found in genes associated with diabetes, the most promising was HNF1A gene (Maturity onset diabetes of the young 3, MODY3) [38,39] where we found as many as four nonsynonymous mutations accumulated in this patient: Ile27Leu (rs1169288) [40][41][42], Ser487Asn (rs2464196) [40,41], Leu551Ser (rs1169304) and Ser581Gly (rs587778398) ( Fig. 4a-d).…”

Section: Discussionmentioning

confidence: 77%

Deciphering genetic signatures by whole exome sequencing in a case of co-prevalence of severe renal hypouricemia and diabetes with impaired insulin secretion

Sekiya¹,

Matsuda²,

Yamamoto³

et al. 2020

BMC Med Genet

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Background: Renal hypouricemia (RHUC) is a hereditary disorder where mutations in SLC22A12 gene and SLC2A9 gene cause RHUC type 1 (RHUC1) and RHUC type 2 (RHUC2), respectively. These genes regulate renal tubular reabsorption of urates while there exist other genes counterbalancing the net excretion of urates including ABCG2 and SLC17A1. Urate metabolism is tightly interconnected with glucose metabolism, and SLC2A9 gene may be involved in insulin secretion from pancreatic β-cells. On the other hand, a myriad of genes are responsible for the impaired insulin secretion independently of urate metabolism. Case presentation: We describe a 67 year-old Japanese man who manifested severe hypouricemia (0.7 mg/dl (3.8-7.0 mg/dl), 41.6 μmol/l (226-416 μmol/l)) and diabetes with impaired insulin secretion. His high urinary fractional excretion of urate (65.5%) and low urinary C-peptide excretion (25.7 μg/day) were compatible with the diagnosis of RHUC and impaired insulin secretion, respectively. Considering the fact that metabolic pathways regulating urates and glucose are closely interconnected, we attempted to delineate the genetic basis of the hypouricemia and the insulin secretion defect observed in this patient using whole exome sequencing. Intriguingly, we found homozygous Trp258* mutations in SLC22A12 gene causing RHUC1 while concurrent mutations reported to be associated with hyperuricemia were also discovered including ABCG2 (Gln141Lys) and SLC17A1 (Thr269Ile). SLC2A9, that also facilitates glucose transport, has been implicated to enhance insulin secretion, however, the nonsynonymous mutations found in SLC2A9 gene of this patient were not dysfunctional variants. Therefore, we embarked on a search for causal mutations for his impaired insulin secretion, resulting in identification of multiple mutations in HNF1A gene (MODY3) as well as other genes that play roles in pancreatic β-cells. Among them, the Leu80fs in the homeobox gene NKX6.1 was an unreported mutation.

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Section: Discussionmentioning

confidence: 77%

Deciphering genetic signatures by whole exome sequencing in a case of co-prevalence of severe renal hypouricemia and diabetes with impaired insulin secretion

Sekiya¹,

Matsuda²,

Yamamoto³

et al. 2020

BMC Med Genet

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“…GCK and HNF1A mutations are known to be the most common mutations, especially in Europe and North America (2,9,18). According to the limited data available in Turkey, HNF1A is regarded as the most common mutation in MODY patients, however there is insufficient information about the clinical characteristics of early-onset T2DM patients and differences from MODY (19).…”

Section: Introductionmentioning

confidence: 99%

When do we need to suspect maturity onset diabetes of the young in patients with type 2 diabetes mellitus?

Üstay¹,

Apaydın²,

Elbasan³

et al. 2022

Archives of Endocrinology and Metabolism

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Objetivo: Maturity onset diabetes of the young (MODY) patients have clinical heterogeneity as shown by many studies. Thus, often it is misdiagnosed to type 1 or type 2 diabetes(T2DM). The aim of this study is to evaluate MODY mutations in adult T2DM patients suspicious in terms of MODY, and to show clinical and laboratory differences between these two situations. Subjects and methods: In this study, we analyzed 72 type 2 diabetic patients and their relatives (35F/37M) who had been suspected for MODY and referred to genetic department for mutation analysis. The gene mutations for MODY have been assessed in the laboratory of Marmara University genetics. Totally 67 (32F/35M; median age 36.1) diabetic patients were analyzed for 7 MODY mutations. Twelve patients who have uncertain mutation (VUS) were excluded from study for further evaluation. MODY(+) (n:30) patients and T2DM patients (n:25) were compared for clinical and laboratory parameters. Results: In MODY(+) subjects, mutations in GCK (MODY 2) (n:12; 40%) were the most common followed by HNF4A (MODY 1) (n:4; 13.3%). Diabetes diagnosis age was younger in MODY(+) group but not statistically significant. Sixty-six percent of MODY(+) subjects had diabetes history at 3-consecutive generations in their family compared with 28% of T2DM patients statistically significant (p:0.006). Gender, BMI, C-peptide, HbA1c, lipid parameters, creatinine, GFR, microalbuminuria, vitamin D and calcium were not statistically different between the groups. Conclusion: According to present study results, MODY mutation positivity is most probable in young autoantibody (-) diabetic patients diagnosed before 30 years of age, who have first degree family history of diabetes.

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“…Previous studies have reported that there is no relationship between this variant and gestational diabetes in Danish ( 69 ), Polish ( 70 ), and Turkish ( 71 ) women. The role of HNF1A p.Ala98Val variant in early and late-onset of diabetes and MODY 3 differs between populations ( 67 , 72 , 73 ).…”

Section: Resultsmentioning

confidence: 99%

Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

et al. 2021

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Introduction/AimsMaturity-Onset Diabetes of the Young (MODY) is a monogenic non-autoimmune diabetes with 14 different genetic forms. MODY-related mutations are rarely found in the Tunisian population. Here, we explored MODY related genes sequences among seventeen unrelated Tunisian probands qualifying the MODY clinical criteria.Materials and MethodsThe GCK and HNF1A genes were systematically analyzed by direct sequencing in all probands. Then, clinical exome sequencing of 4,813 genes was performed on three unrelated patients. Among them, 130 genes have been reported to be involved in the regulation of glucose metabolism, β-cell development, differentiation and function. All identified variants were analyzed according to their frequencies in the GnomAD database and validated by direct sequencing.ResultsWe identified the previously reported GCK mutation (rs1085307455) in one patient. The clinical features of the MODY2 proband were similar to previous reports. In this study, we revealed rare and novel alterations in GCK (rs780806456) and ABCC8 (rs201499958) genes with uncertain significance. We also found two likely benign alterations in HNF1A (rs1800574) and KLF11 (rs35927125) genes with minor allele frequencies similar to those depicted in public databases. No pathogenic variants have been identified through clinical exome analysis.ConclusionsThe most appropriate patients were selected, following a strict clinical screening approach, for genetic testing. However, the known MODY1-13 genes could not explain most of the Tunisian MODY cases, suggesting the involvement of unidentified genes in the majority of Tunisian affected families.

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HNF1A gene p.I27L is associated with early-onset, maturity-onset diabetes of the young-like diabetes in Turkey

Cited by 13 publications

References 32 publications

Deciphering genetic signatures by whole exome sequencing in a case of co-prevalence of severe renal hypouricemia and diabetes with impaired insulin secretion

Deciphering genetic signatures by whole exome sequencing in a case of co-prevalence of severe renal hypouricemia and diabetes with impaired insulin secretion

When do we need to suspect maturity onset diabetes of the young in patients with type 2 diabetes mellitus?

Tunisian Maturity-Onset Diabetes of the Young: A Short Review and a New Molecular and Clinical Investigation

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