Functional characterization of p.Pro409His variant in HNF1A, a hypomorphic mutation involved in pancreatic β-cell dysfunction

Nocera, Donatella; Menniti, Miranda; Belviso, Stefania; Bond, Heather M.; Lanzillotta, Delia; Spoleti, Cristina Barbara; Guagliardi, Maria Rosaria; Malatesta, Paola; Trapasso, Francesco; Irace, Concetta; Perrotti, Nicola; Iuliano, Rodolfo

doi:10.1007/s00592-019-01298-6

Cited by 3 publications

(3 citation statements)

References 29 publications

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“…SNP mutations may affect the function of the HNF1a protein through the following mechanisms: 1) Affecting the ability of DNA to bind the transcriptional regulatory region of the target gene; 2) Affecting the transcriptional activity of HNF1a; 3) Affecting the nuclear entry ability of the HNF1a protein; 4) Affecting the stability of the HNF1a protein; and 5) Affecting the expression of the HNF1a protein, especially SNPs located in the promoter region (107,125,133). In 2017, Najmi et al found that the transcriptional activity or DNA binding ability of HNF1a variants that cause T2D was between those of normal wild-type protein and the HNF1A-MODY variant (134).…”

Section: Relationship Between Hnf1a and Different Types Of Diabetesmentioning

confidence: 99%

“…HNF1A-MODY3 is characterized by not only gene heterogeneity but also phenotype heterogeneity. For example, the two human variants HNF1α (P408H) and HNF1α (P409H) can be considered different variants ( 125 , 126 ). A possible reason is that these two adjacent sites regulate the promoters of two different HNF1A-targeted genes.…”

Section: Relationship Between Hnf1a and Different Types Of Diabetesmentioning

confidence: 99%

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HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus

Jiang

Sun

2022

Front. Endocrinol.

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Diabetes, a disease characterized by hyperglycemia, has a serious impact on the lives and families of patients as well as on society. Diabetes is a group of highly heterogeneous metabolic diseases that can be classified as type 1 diabetes (T1D), type 2 diabetes (T2D), gestational diabetes mellitus (GDM), or other according to the etiology. The clinical manifestations are more or less similar among the different types of diabetes, and each type is highly heterogeneous due to different pathogenic factors. Therefore, distinguishing between various types of diabetes and defining their subtypes are major challenges hindering the precise treatment of the disease. T2D is the main type of diabetes in humans as well as the most heterogeneous. Fortunately, some studies have shown that variants of certain genes involved in monogenic diabetes also increase the risk of T2D. We hope this finding will enable breakthroughs regarding the pathogenesis of T2D and facilitate personalized treatment of the disease by exploring the function of the signal genes involved. Hepatocyte nuclear factor 1 homeobox A (HNF1α) is widely expressed in pancreatic β cells, the liver, the intestines, and other organs. HNF1α is highly polymorphic, but lacks a mutation hot spot. Mutations can be found at any site of the gene. Some single nucleotide polymorphisms (SNPs) cause maturity-onset diabetes of the young type 3 (MODY3) while some others do not cause MODY3 but increase the susceptibility to T2D or GDM. The phenotypes of MODY3 caused by different SNPs also differ. MODY3 is among the most common types of MODY, which is a form of monogenic diabetes mellitus caused by a single gene mutation. Both T2D and GDM are multifactorial diseases caused by both genetic and environmental factors. Different types of diabetes mellitus have different clinical phenotypes and treatments. This review focuses on HNF1α gene polymorphisms, HNF1A-MODY3, HNF1A-associated T2D and GDM, and the related pathogenesis and treatment methods. We hope this review will provide a valuable reference for the precise and individualized treatment of diabetes caused by abnormal HNF1α by summarizing the clinical heterogeneity of blood glucose abnormalities caused by HNF1α mutation.

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Section: Relationship Between Hnf1a and Different Types Of Diabetesmentioning

confidence: 99%

Section: Relationship Between Hnf1a and Different Types Of Diabetesmentioning

confidence: 99%

HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus

Jiang

Sun

2022

Front. Endocrinol.

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“…Rare variants were defined as those that had a minor allele frequency ≤1% in any ancestry in the Genome Aggregation Database (gnomAD). Importantly, we retained variants that have previously been shown to impair luciferase-based transactivation or nuclear localisation to ≤60% of wild-type function [9,[21][22][23][24][25] (ESM Fig. 2 and ESM Table 1).…”

Section: Hnf1a Variant Classificationmentioning

confidence: 99%

The contribution of functional HNF1A variants and polygenic susceptibility to risk of type 2 diabetes in ancestrally diverse populations

et al. 2022

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Aims/hypothesis We examined the contribution of rare HNF1A variants to type 2 diabetes risk and age of diagnosis, and the extent to which their impact is affected by overall genetic susceptibility, across three ancestry groups. Methods Using exome sequencing data of 160,615 individuals of the UK Biobank and 18,797 individuals of the BioMe Biobank, we identified 746 carriers of rare functional HNF1A variants (minor allele frequency ≤1%), of which 507 carry variants in the functional domains. We calculated polygenic risk scores (PRSs) based on genome-wide association study summary statistics for type 2 diabetes, and examined the association of HNF1A variants and PRS with risk of type 2 diabetes and age of diagnosis. We also tested whether the PRS affects the association between HNF1A variants and type 2 diabetes risk by including an interaction term. Results Rare HNF1A variants that are predicted to impair protein function are associated with increased risk of type 2 diabetes in individuals of European ancestry (OR 1.46, p=0.049), particularly when the variants are located in the functional domains (OR 1.89, p=0.002). No association was observed for individuals of African ancestry (OR 1.10, p=0.60) or Hispanic-Latino ancestry (OR 1.00, p=1.00). Rare functional HNF1A variants were associated with an earlier age at diagnosis in the Hispanic-Latino population (β=−5.0 years, p=0.03), and this association was marginally more pronounced for variants in the functional domains (β=−5.59 years, p=0.03). No associations were observed for other ancestries (African ancestry β=−2.7 years, p=0.13; European ancestry β=−3.5 years, p=0.20). A higher PRS was associated with increased odds of type 2 diabetes in all ancestries (OR 1.61–2.11, p<10−5) and an earlier age at diagnosis in individuals of African ancestry (β=−1.4 years, p=3.7 × 10−6) and Hispanic-Latino ancestry (β=−2.4 years, p<2 × 10−16). Furthermore, a higher PRS exacerbated the effect of the functional HNF1A variants on type 2 diabetes in the European ancestry population (pinteraction=0.037). Conclusions/interpretation We show that rare functional HNF1A variants, in particular those located in the functional domains, increase the risk of type 2 diabetes, at least among individuals of European ancestry. Their effect is even more pronounced in individuals with a high polygenic susceptibility. Our analyses highlight the importance of the location of functional variants within a gene and an individual’s overall polygenic susceptibility, and emphasise the need for more genetic data in non-European populations. Graphical abstract

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An intron mutation of HNF1A causes abnormal splicing and impairs its activity as a transcription factor

Wang

Hua

Xie

et al. 2022

Molecular and Cellular Endocrinology

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Functional characterization of p.Pro409His variant in HNF1A, a hypomorphic mutation involved in pancreatic β-cell dysfunction

Cited by 3 publications

References 29 publications

HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus

HNF1A：From Monogenic Diabetes to Type 2 Diabetes and Gestational Diabetes Mellitus

The contribution of functional HNF1A variants and polygenic susceptibility to risk of type 2 diabetes in ancestrally diverse populations

An intron mutation of HNF1A causes abnormal splicing and impairs its activity as a transcription factor

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