Mutations in hepatocyte nuclear factor-1  and their related phenotypes

Edghill, Emma L.; Bingham, Coralie; Ellard, Sian; Hattersley, Andrew T.

doi:10.1136/jmg.2005.032854

Cited by 307 publications

(333 citation statements)

References 40 publications

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“…The age of presentation was more suggestive of GCK MODY, as other MODY subtypes often present in adolescence and young adulthood; however, this condition did not explain the early retinopathy in his father from whom he inherited the diabetes. The absence of renal cysts and other extrapancreatic features ruled out the possibility of HNF-1a MODY 1112…”

Section: Discussionmentioning

confidence: 99%

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

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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.

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Section: Discussionmentioning

confidence: 99%

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

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“…Several of the patients had additional paramesonephric duct malformations (apart from common channel anomalies), such as fusion defects of the uterus and rudimentary uterine horns. Human dominant HNF1β mutations cause the Renal Cysts and Diabetes syndrome that always features a renal malformation (including congenital solitary and horseshoe kidney, renal cystic dysplasia and glomerulocystic disease); in addition, some females have defects of paramesonephric duct differentiation (bicornuate uterus, uterus didelphys and hemi-uterus) (27)(28)(29). The human clinical genetic observations, together with the fact that HNF1β is expressed during normal development of the mammalian kidney and uterus (25,26) led us to believe that HNF1β was another excellent candidate gene to screen in patients with persistent cloaca.…”

Section: Discussionmentioning

confidence: 99%

“…For HNF1β (nine exons) sequencing was performed as described (29). For EFNB2 (five exons) sequencing, first total genomic DNA was whole genome-amplified using the GenomiPhi™ DNA Amplification kit (Amersham Biosciences, Piscataway, NJ, USA).…”

Section: Sequencingmentioning

confidence: 99%

“…In addition, we screened three other genes, Sonic Hedgehog (SHH: 7q36), Ephrin B2 (EFNB2: 13q33) and Hepatocyte Nuclear Factor 1 β(HNF1β: 17cen-q21.3). As detailed in the Discussion, SHH (8,17,(21)(22)(23), EFNB2 (24) and HNF1β (25)(26)(27)(28)(29) are expressed in the developing renal, genital and alimentary tracts, and have been functionally implicated in the normal development of these structures.…”

Section: Introductionmentioning

confidence: 99%

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Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

Jenkins

Bitner‐Glindzicz

Thomasson

et al. 2007

Journal of Pediatric Urology

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Objectives-'Persistent cloaca' is a severe malformation affecting females in which the urinary, genital and alimentary tracts share a single conduit. Previously, a Uroplakin IIIA (UPIIIA) mutation was reported in one individual with persistent cloaca, and UPIIIA, Sonic Hedgehog (SHH), Ephrin B2 (EFNB2) and Hepatocyte Nuclear Factor 1β (HNF1β) are expressed during the normal development of organs that are affected in this condition. HNF1β mutations have been associated with uterine malformations in humans, and mutations of genes homologous to human SHH or EFNB2 cause persistent cloaca in mice.Patients and Methods-We sought mutations of coding regions of UPIIIA, SHH, EFNB2 and HNF1β genes by direct sequencing in a group of 20 patients with persistent cloaca. Most had associated malformations of the upper renal tract and over half had impaired renal excretory function. The majority of patients had congenital anomalies outside the renal/genital tracts and two had the VACTERL association.Results-Apart from a previously described index case, we failed to find UPIIIA mutations, and no patient had a SHH, EFNB2 or HNF1β mutation.Conclusion-Persistent cloaca is only rarely associated with UPIIIA mutation. Despite the fact that SHH and EFNB2 are appealing candidate genes, based on their expression patterns and mutant mice phenotypes, they were not mutated in these humans with persistent cloaca. Although HNF1β mutations can perturb paramesonephric duct fusion in humans, HNF1β was not mutated in persistent cloaca.

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“…We know most about the role of HNF1B in diabetes because of the work following its discovery as a MODY gene, and later as a gene involved in renal disease and other abnormalities [25]. HNF1B is also involved in neoplasia.…”

Section: Two Gene Loci Three Variants and Two Diseasesmentioning

confidence: 99%

A genetic link between type 2 diabetes and prostate cancer

2008

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Epidemiological studies suggest that men with type 2 diabetes are less likely than non-diabetic men to develop prostate cancer. The cause of this association is not known. Recent genetic studies have highlighted a potential genetic link between the two diseases. Two studies have identified a version (allele) of a variant in the HNF1B (also known as TCF2) gene that predisposes to type 2 diabetes, and one of them showed that the same allele protects men from prostate cancer. Other, separate, studies have identified different variants in the JAZF1 gene, one associated with type 2 diabetes, another associated with prostate cancer. These findings are unlikely to completely explain the epidemiological association between the two diseases but they provide new insight into a possible direct causal link, rather than one that is confounded or biased in some way. There is extensive but conflicting literature on whether diabetes mellitus is associated with protection from prostate cancer. The extent to which bias and confounding factors could influence this association is also unclear. The most comprehensive meta-analysis performed to date found an inverse association between diabetes and prostate cancer (RR 0.84, 95% CI 0.76-0.93) [1], but there was significant heterogeneity between studies (p<0.01). Adjustment for covariates, including BMI, strengthened the association. Two studies reported since this meta-analysis both showed evidence for a reduced risk of prostate cancer in men with type 2 diabetes. The Prostate Cancer Prevention Trial found that diabetes was associated with a 47% reduced risk of low-grade prostate cancer and a 28% reduced risk of high-grade prostate cancer [2]. In another large prospective cohort analysis, diabetes was associated with a 31% lower risk of prostate cancer [3].Some data suggest that a reduced incidence of prostate cancer is more pronounced in those with a longstanding elevated risk reported in the first few years after the diagnosis of diabetes [4,5]. However, another study found the opposite; in the 1959-1972 Cancer Prevention Study there was no overall association between diabetes and prostate cancer incidence, but those with diabetes for 5 or more years had a higher incidence of prostate cancer than did men without diabetes [6].The data on the association of either obesity or metabolic syndrome with prostate cancer incidence are also inconsistent. Both elevated and reduced risks have been reported in

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Mutations in hepatocyte nuclear factor-1 and their related phenotypes

Cited by 307 publications

References 40 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

Mutational analyses of UPIIIA, SHH, EFNB2, and HNF1β in persistent cloaca and associated kidney malformations

A genetic link between type 2 diabetes and prostate cancer

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