A low renal threshold for glucose in diabetic patients with a mutation in the hepatocyte nuclear factor-1α (HNF-1α) gene

Menzel, R; Kaisaki, Pamela J.; Rjasanowski, I; Heinke, P.; Kerner, W.; Menzel, Stephan

doi:10.1002/(sici)1096-9136(199810)15:10<816::aid-dia714>3.0.co;2-p

Cited by 114 publications

(84 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Both MODY 1 (HNF-4a) and MODY 3 (HNF-1a) have similar phenotype, as HNF-4a regulates the expression of HNF-1a, but the latter is more common and is associated with a low renal threshold for glucose resulting in glycosuria at a relatively low blood glucose concentration,1314 which was detected in our patient. We performed OGTT as the response to this test can differentiate between HNF-1a and GCK MODY 15.…”

Section: Discussionmentioning

confidence: 58%

Response to oral gliclazide in a pre-pubertal child with hepatic nuclear factor-1 alpha maturity onset diabetes of the young

Habeb

George

Hattersley

2011

Annals of Saudi Medicine

View full text Add to dashboard Cite

The term “maturity onset diabetes of the young” (MODY) describes a heterogeneous group of monogenic diabetes of which hepatic nuclear factor-1 alpha (HNF-1α) MODY is the most common. Patients with HNF-1α mutations typically present after puberty, and oral sulfonylureas (SU) have been shown to be effective in adults with this condition. A 7-year-old boy presented with asymptomatic hyperglycemia ranging between 6.2 and 10.1 mmol/L and glycosuria for nearly a year. The child's initial HbA1c was 6.9% and the pancreatic Islet cell autoantibodies were negative. His response to the oral glucose tolerance test (OGTT) showed a large increment of glucose from basal level of 7.7 to 21.1 mmol/L in 120 min. The mild presentation, family history, and negative autoantibodies were suggestive of HNF-1α MODY, which was confirmed by mutation analysis. Initial management with diet alone was not sufficient, but he responded well to 20 mg oral gliclazide once a day with an improvement of HbA1C from 7.2% to 6.5% within 3 months of treatment. The case is an illustration of the clinical utility of molecular genetic tests in the management of childhood diabetes.

show abstract

Section: Discussionmentioning

confidence: 58%

Response to oral gliclazide in a pre-pubertal child with hepatic nuclear factor-1 alpha maturity onset diabetes of the young

Habeb

George

Hattersley

2011

Annals of Saudi Medicine

View full text Add to dashboard Cite

show abstract

“…Like in other studies (10,11), disease phenotype was highly variable in the cohort. The majority of patients presented with hyperglycaemia at disease onset and specific symptoms including polydipsia, polyuria or glucosuria were reported for one fifth of patients.…”

Section: Discussionmentioning

confidence: 99%

Genetic and clinical characteristics of patients with HNF1A gene variations from the German–Austrian DPV database

Awa

Thon²,

Raile³

et al. 2011

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: To determine prevalence, genetic and phenotype characteristics of patients with hepatocyte nuclear factor-1a (HNF1A) variants in the Diabetes Patienten Verlaufsdokumenation (DPV) multicentre database and to examine the influence of HNF1A mutation type, or location on clinical phenotypes. Patients and methods: Seventy-one DPV patients were labelled as HNF1A-MODY (MODY3). Forty-four patients carried HNF1A mutations, while 27 patients were found to have HNF1A polymorphisms only. Associations between mutation type/position and age at disease onset, HbAlc, body mass index (BMI), diagnosis, family history and treatment modality were analysed using non-parametric statistics (Wilcoxon test). Results: Patients with HNF1A mutations were 36% male, aged 14.1G5.8 years at diagnosis, and slightly overweight (BMI-SDS: C0.8G1.1). Treatment was lifestyle intervention (20.5%), insulin (35.3%), oral anti-diabetic (OAD, 43%) and both insulinCOAD (15.9%). More patients with missense mutations (60%) than patients with nonsense mutations/frameshift (23.8%) did not use insulin (PZ0.03). No differences were found with regard to mutation types, isoform or domain. We identified several previously undescribed mutations in the cohort including c.-158insGGGTTGG in the promoter region, G31X, E41X, Q130X, L162P, R245I, A269P, S355X, Q398X, Q473X, Q495X, E508X, P588fs-insGCCA and P588fs-delAC. Patients carrying HNF1A polymorphisms were significantly younger at diagnosis than patients with HNF1A mutations (10.9G4.2 vs 14.19G5.8 years; PZ0.027), and all carried I27L, S487N and A98V (nZ3). Conclusion: HNF1A-MODY is the second most frequent MODY diagnosis registered in the DPV database, and previously undescribed HNF1A mutations account for about one-third of HNF1A-MODY cases. Patients with HNF1A polymorphisms documented as HNF1A-MODY were misclassified. They may have autoantibody-negative type 1B or type 2 diabetes or may have other MODY types.

show abstract

“…Mutations in the human HNF1␣ gene (reviewed in ref. 16) do not affect kidney morphogenesis but may alter renal glucose reabsorption (34), whereas mutations in the human HNF1␤ gene can lead to severe renal malformations that are present early in fetal development (12)(13)(14)(15). A clear functional distinction between the two members of the HNF1 family also is observed in knock-out mice, where the homozygous inactivation of the HNF1␣ gene affects only postnatal development, including hepatic dysfunction, a renal Fanconi syndrome, defective pancreatic insulin secretion, and dwarfism (35)(36)(37), whereas the corresponding knock-out of the HNF1␤ gene leads to embryonic lethality by impaired ectoderm and endoderm differentiation (10,11).…”

Section: Discussionmentioning

confidence: 99%

The mutated human gene encoding hepatocyte nuclear factor 1β inhibits kidney formation in developing Xenopus embryos

Wild

Strandmann

Nastos

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The transcription factor hepatocyte nuclear factor 1␤ (HNF1␤) is a tissue-specific regulator that also plays an essential role in early development of vertebrates. In humans, four heterozygous mutations in the HNF1␤ gene have been identified that lead to early onset of diabetes and severe primary renal defects. The degree and type of renal defects seem to depend on the specific mutation. We show that the frameshift mutant P328L329fsdelCCTCT associated with nephron agenesis retains its DNA-binding properties and acts as a gain-of-function mutation with increased transactivation potential in transfection experiments. Expression of this mutated factor in the Xenopus embryo leads to defective development and agenesis of the pronephros, the first kidney form of amphibians. Very similar defects are generated by overexpressing in Xenopus the wild-type HNF1␤, which is consistent with the gain-of-function property of the mutant. In contrast, introduction of the human HNF1␤ mutant R137-K161del, which is associated with a reduced number of nephrons with hypertrophy of the remaining ones and which has an impaired DNA binding, shows only a minor effect on pronephros development in Xenopus. Thus, the overexpression of both human mutants has a different effect on renal development in Xenopus, reflecting the variation in renal phenotype seen with these mutations. We conclude that mutations in human HNF1␤ can be functionally characterized in Xenopus. Our findings imply that HNF1␤ not only is an early marker of kidney development but also is functionally involved in morphogenetic events, and these processes can be investigated in lower vertebrates.

show abstract

A low renal threshold for glucose in diabetic patients with a mutation in the hepatocyte nuclear factor-1α (HNF-1α) gene

Cited by 114 publications

References 16 publications

Response to oral gliclazide in a pre-pubertal child with hepatic nuclear factor-1 alpha maturity onset diabetes of the young

Response to oral gliclazide in a pre-pubertal child with hepatic nuclear factor-1 alpha maturity onset diabetes of the young

Genetic and clinical characteristics of patients with HNF1A gene variations from the German–Austrian DPV database

The mutated human gene encoding hepatocyte nuclear factor 1β inhibits kidney formation in developing Xenopus embryos

Contact Info

Product

Resources

About