Monogenic diabetes, renal dysplasia and hypopituitarism: a patient with a HNF1A mutation

Simms, RJ; Sayer, John A.; Quinton, Richard; Walker, Mark S.; Ellard, Sian; Goodship, Tim

doi:10.1093/qjmed/hcq195

Cited by 5 publications

(4 citation statements)

References 13 publications

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“…The expression of HNF1A and HNF1B was detectable in the kidneys during early development [ 9 ]. HNF1B mutations cause developmental kidney diseases, including renal cysts, single kidneys, renal hypoplasia, and electrolyte abnormalities [ 31 ], whereas the majority of HNF1A mutations are not associated with abnormal kidney morphology [ 32 , 33 ]. It has been observed that the reabsorption of urinary glucose is lower in patients with MODY3 than in those with type 1 and type 2 diabetes [ 34 , 35 ].…”

Section: Extrapancreatic Organs and Hnf1amentioning

confidence: 99%

HNF1A Mutations and Beta Cell Dysfunction in Diabetes

Miyachi

Miyazawa

Ogawa

2022

IJMS

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Understanding the genetic factors of diabetes is essential for addressing the global increase in type 2 diabetes. HNF1A mutations cause a monogenic form of diabetes called maturity-onset diabetes of the young (MODY), and HNF1A single-nucleotide polymorphisms are associated with the development of type 2 diabetes. Numerous studies have been conducted, mainly using genetically modified mice, to explore the molecular basis for the development of diabetes caused by HNF1A mutations, and to reveal the roles of HNF1A in multiple organs, including insulin secretion from pancreatic beta cells, lipid metabolism and protein synthesis in the liver, and urinary glucose reabsorption in the kidneys. Recent studies using human stem cells that mimic MODY have provided new insights into beta cell dysfunction. In this article, we discuss the involvement of HNF1A in beta cell dysfunction by reviewing previous studies using genetically modified mice and recent findings in human stem cell-derived beta cells.

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Section: Extrapancreatic Organs and Hnf1amentioning

confidence: 99%

HNF1A Mutations and Beta Cell Dysfunction in Diabetes

Miyachi

Miyazawa

Ogawa

2022

IJMS

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“…Other abnormalities include infantile uterus and unidentifiable ovaries, leading to infertility -a phenotype also observed in Hnf1a-null mice. 94,97 Hnf1a-null mice also develop abnormalities in the reproductive system, rendering them sterile. 94,95 One reason for the observed glycosuria (excretion of glucose into the urine) could be a low renal threshold for glucose, possibly because of decreased expression of SGLT2 (SLC5A2) and decreased glucose reabsorption in the proximal tubules.…”

Section: Hnf1a Mutations In Mice and Menmentioning

confidence: 99%

The molecular functions of hepatocyte nuclear factors – In and beyond the liver

Lau

Loo

et al. 2018

Journal of Hepatology

193

191

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The hepatocyte nuclear factors (HNFs) namely HNF1α/β, FOXA1/2/3, HNF4α/γ and ONECUT1/2 are expressed in a variety of tissues and organs, including the liver, pancreas and kidney. The spatial and temporal manner of HNF expression regulates embryonic development and subsequently the development of multiple tissues during adulthood. Though the HNFs were initially identified individually based on their roles in the liver, numerous studies have now revealed that the HNFs cross-regulate one another and exhibit synergistic relationships in the regulation of tissue development and function. The complex HNF transcriptional regulatory networks have largely been elucidated in rodent models, but less so in human biological systems. Several heterozygous mutations in these HNFs were found to cause diseases in humans but not in rodents, suggesting clear species-specific differences in mutational mechanisms that remain to be uncovered. In this review, we compare and contrast the expression patterns of the HNFs, the HNF cross-regulatory networks and how these liver-enriched transcription factors serve multiple functions in the liver and beyond, extending our focus to the pancreas and kidney. We also summarise the insights gained from both human and rodent studies of mutations in several HNFs that are known to lead to different disease conditions.

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“…Mutations in the HNF1A gene are associated with MODY3, which is characterized by impaired insulin secretion, retention of sensitivity to sulfonylureas, and a decrease in the renal threshold for glucose. Cases of liver adenomatosis, renal dysplasia, and hypopituitarism in carriers of these mutations have been documented [41,42]. The clinical manifestations of MODY3 can vary within the same family and among unrelated mutation carriers.…”

Section: Discussionmentioning

confidence: 99%

The Mutation Spectrum of Maturity Onset Diabetes of the Young (MODY)-Associated Genes among Western Siberia Patients

Ivanoshchuk

Shakhtshneider

Rymar

et al. 2021

JPM

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Maturity onset diabetes of the young (MODY) is a congenital form of diabetes characterized by onset at a young age and a primary defect in pancreatic-β-cell function. Currently, 14 subtypes of MODY are known, and each is associated with mutations in a specific gene: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, KCNJ11, ABCC8, and APPL1. The most common subtypes of MODY are associated with mutations in the genes GCK, HNF1A, HNF4A, and HNF1B. Among them, up to 70% of cases are caused by mutations in GCK and HNF1A. Here, an analysis of 14 MODY genes was performed in 178 patients with a MODY phenotype in Western Siberia. Multiplex ligation-dependent probe amplification analysis of DNA samples from 50 randomly selected patients without detectable mutations did not reveal large rearrangements in the MODY genes. In 38 patients (37% males) among the 178 subjects, mutations were identified in HNF4A, GCK, HNF1A, and ABCC8. We identified novel potentially causative mutations p.Lys142*, Leu146Val, Ala173Glnfs*30, Val181Asp, Gly261Ala, IVS7 c.864 −1G>T, Cys371*, and Glu443Lys in GCK and Ser6Arg, IVS 2 c.526 +1 G>T, IVS3 c.713 +2 T>A, and Arg238Lys in HNF1A.

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Monogenic diabetes, renal dysplasia and hypopituitarism: a patient with a HNF1A mutation

Cited by 5 publications

References 13 publications

HNF1A Mutations and Beta Cell Dysfunction in Diabetes

HNF1A Mutations and Beta Cell Dysfunction in Diabetes

The molecular functions of hepatocyte nuclear factors – In and beyond the liver

The Mutation Spectrum of Maturity Onset Diabetes of the Young (MODY)-Associated Genes among Western Siberia Patients

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