Mutations in the Hepatocyte Nuclear Factor–1α Gene Are a Common Cause of Maturity-Onset Diabetes of the Young in the U.K.

Frayling, Timothy M.; Bulman, Michael P.; Ellard, Sian; Appleton, Maggie; Dronsfield, M. J.; Mackie, Anna; Baird, J. D.; Kaisaki, Pamela J.; Yamagata, Kazuya; Bell, Graeme I.; Bain, Stephen C.; Hattersley, Andrew T.

doi:10.2337/diab.46.4.720

Cited by 178 publications

(115 citation statements)

References 19 publications

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“…Mutations in the gene encoding for the HNF-1α are associated with MODY type 3, which is the most common form of MODY in the white population 34. More than 350 mutations have been identified in the HNF-1α gene leading to variable clinical expression and age of presentation 5.…”

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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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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 RW pedigree includes 7 subjects who have inherited the nonsense mutation Q268X but still have normal glucose tolerance and while 5 of them are less than 25 years of age, 2 individuals are aged 36 and 44 [6]. The penetrance of HNF-1a mutations appears higher; we identified 69 UK subjects with HNF-1a mutations, 64 were diabetic (mean of diagnosis 22.5 years) and only 2 (3 %) had normal fasting blood glucose levels at the age of 25 years (and aged 26 and 42) [10]. The suggestion of a lower penetrance of HNF4a mutations may mean that primary prevention or delaying the onset of diabetes is easier than in HNF1a pedigrees.…”

Section: Discussionmentioning

confidence: 97%

A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young

et al. 1997

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Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin-dependent diabetes mellitus (NIDDM) characterised by an early age of onset (< 25 years) and an autosomal dominant mode of inheritance [1,2]. In a family diabetes results from a single heterozygous mutation but the condition is genetically heterogeneous with three different genes identified to date; hepatocyte nuclear factor 4 alpha (HNF-4a) [3], glucokinase [4,5] and hepatocyte nuclear factor 1 alpha (HNF-1a) [6] corresponding to the MODY1, MODY2 and MODY3 loci, respectively. At least one further gene has not yet been localised.The first breakthrough in the molecular genetics of MODY was by Bell and colleagues in 1991 [7]; they showed linkage between diabetes and markers on chromosome 20q adjacent to the adenosine deaminase gene in a large North American pedigree of European extraction (the RW pedigree). This gene, designated MODY1, was localised by further mapping to a 13 Mb region of 20q 11.2-13.1 [8]. This locus is a rare cause of MODY with only one pedigree in the literature showing weak evidence of linkage to MODY1 (ADA lod score 1.14 at v = 0, in pedigree F30 with 17 subjects, 6 of whom are diabetic) [4]. Fine mapping of the gene was difficult because of the low number of families available. The identification of the MODY1 gene was facilitated by the recent discovery that MODY3 on chromosome 12q was caused by mutations in the hepatocyte nuclear factor 1a (HNF-1a), a transcription factor expressed in a number of tissues including the islets of Langerhans Diabetologia (1997) 40: 859-862 Rapid communicationsA missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young . A nonsense mutation in the HNF-4a gene has recently been shown to cause MODY in a single large North American pedigree (RW). We screened a large UK Caucasian MODY family which showed weak evidence of linkage to the MODY1 locus on chromosome 20q (lod score for ADA 0.68 at v = 0) for mutations in the coding region of the HNF-4a gene by direct sequencing. A missense mutation resulting in the substitution of glutamine for glutamic acid was identified in exon 7 (E276Q). The mutation was present in all of the diabetic members of the pedigree plus two unaffected subjects and was not detected in 75 normal control subjects or 95 UK Caucasian subjects with late-onset NIDDM. This is the first missense mutation to be described in the HNF-4a gene. [Diabetologia (1997)

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“…We also identified a novel L518P519fsTCC→A mutation in three unrelated families. The P291fsinsC mutation is the most common cause of MODY3 in Caucasian subjects [12,13,14]. In 60 MODY probands, eight (13%) had the P291fsinsC mutation [14].…”

Section: Discussionmentioning

confidence: 99%

Identification of three new mutations of the HNF-1 α gene in Japanese MODY families

et al. 2002

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Aim/hypothesis. We analysed Japanese MODY patients for mutations in the HNF-1α gene. Methods. Fifty unrelated Japanese patients with earlyonset diabetes (diagnosed at 25 years of age or younger) or with a strong family history of diabetes were screened for mutations in the HNF-1α gene. Functional studies of the mutant HNF-1α were carried out. Results. We identified three new mutations in the HNF-1α gene in the families with a strong family history for diabetes. One mutation (L518P519fsTCC→A) was identified in three unrelated families, while the other two mutations (T521I and V617I) were identified in one family. We also identified the A site of the promoter (+102G-to-C), which was reported previously. We examined the functional properties of the mutant HNF-1α. By increasing the amount of L518P519fsTCC→A-HNF-1α, increasing inhibition of the transcription of human transthyretin (TTR) was observed (up to 61% of the control). Increasing amounts of T521I-HNF-1α or V617I-HNF-1α mutant proteins increased TTR promoter transcription up to 4.3-fold and 2.4-fold, respectively, whereas both increased transcription up to 12.4-fold of the control. Conclusion/interpretation. The L518P519fsTCC→A was identified for the first time and this mutation might be a common cause of Japanese MODY3 in Okinawa area. In addition, both the T521I and V617I mutations were present in two patients in the same family. Since the prevalence of these mutations is relatively high (10%, 5/50), the HNF-1α gene needs to be screened for mutations in patients either with earlyonset diabetes or with a strong family history for diabetes. [Diabetologia (2002[Diabetologia ( ) 45:1713[Diabetologia ( -1718 Keywords MODY, HNF-1α, mutation, Japanese, gain-of-function.

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Mutations in the Hepatocyte Nuclear Factor–1α Gene Are a Common Cause of Maturity-Onset Diabetes of the Young in the U.K.

Cited by 178 publications

References 19 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

A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young

Identification of three new mutations of the HNF-1 α gene in Japanese MODY families

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