Identifying Hepatic Nuclear Factor 1α Mutations in Children and Young Adults With a Clinical Diagnosis of Type 1 Diabetes

Lambert, Aude; Ellard, Sian; Allen, Lisa; Gallen, Ian W.; Gillespie, Kathleen M.; Bingley, Polly J.; Hattersley, Andrew T.

doi:10.2337/diacare.26.2.333

Cited by 75 publications

(61 citation statements)

References 22 publications

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“…Some MODY patients may be misdiagnosed as having type 1 diabetes because they present with polydipsia, polyuria, and weight loss in their late teens or early 20s with a blood glucose level of 15-20 mmol/liter (normal range 4-6 mmol/liter) and are treated immediately with insulin. Studies of patients diagnosed with type 1 diabetes who have an affected first degree relative have found HNF1A gene mutations in 5 to 10% of patients depending upon additional selection criteria such as non-high-risk HLA haplotype, negative autoantibody status, or three generations of diabetes [Lambert et al, 2003;Moller et al, 1998;Yamada et al, 1997a].…”

Section: Di¡erential Diagnosis Of Type 1 and Type 2 Diabetes Vs Modymentioning

confidence: 99%

Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young

2006

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Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes mellitus characterized by autosomal dominant inheritance, early age of onset (often <25 years of age), and pancreatic beta-cell dysfunction. MODY is both clinically and genetically heterogeneous, with six different genes identified to date; glucokinase (GCK), hepatocyte nuclear factor-1 alpha (HNF1A, or TCF1), hepatocyte nuclear factor-4 alpha (HNF4A), insulin promoter factor-1 (IPF1 or PDX1), hepatocyte nuclear factor-1 beta (HNF1B or TCF2), and neurogenic differentiation 1 (NEUROD1). Mutations in the HNF1A gene are a common cause of MODY in the majority of populations studied. A total of 193 different mutations have been described in 373 families. The most common mutation is Pro291fs (P291fsinsC) in the polycytosine (poly C) tract of exon 4, which has been reported in 65 families. HNF4A mutations are rarer; 31 mutations reported in 40 families. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The identification of an HNF1A or 4A gene mutation confirms a diagnosis of MODY and has important implications for clinical management.

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Section: Di¡erential Diagnosis Of Type 1 and Type 2 Diabetes Vs Modymentioning

confidence: 99%

Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young

2006

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“…We previously reported a patient with an HNF-1␣ mutation who was GAD antibody negative and homozygous for a protective HLA haplotype, not supporting the diagnosis of type 1 diabetes. The identification of a specific genetic etiology can have implications for treatment; in this case, an affected family member was taken off insulin and is now treated with a sulfonylurea (7).…”

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Activating Mutations in the KCNJ11 Gene Encoding the ATP-Sensitive K+ Channel Subunit Kir6.2 Are Rare in Clinically Defined Type 1 Diabetes Diagnosed Before 2 Years

et al. 2004

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We have recently shown that permanent neonatal diabetes can be caused by activating mutations in KCNJ11 that encode the Kir6.2 subunit of the ␤-cell ATP-sensitive K ؉ channel. Some of these patients were diagnosed after 3 months of age and presented with ketoacidosis and marked hyperglycemia, which could have been diagnosed as type 1 diabetes. We hypothesized that KCNJ11 mutations could present clinically as type 1 diabetes. We screened the KCNJ11 gene for mutations in 77 U.K. type 1 diabetic subjects diagnosed under the age of 2 years. One patient was found to be heterozygous for the missense mutation R201C. She had low birth weight, was diagnosed at 5 weeks, and did not have a high risk predisposing HLA genotype. A novel variant, R176C, was identified in one diabetic subject but did not cosegregate with diabetes within the family. In conclusion, we have shown that heterozygous activating mutations in the KCNJ11 gene are a rare cause of clinically defined type 1 diabetes diagnosed before 2 years. Although activating KCNJ11 mutations are rare in patients diagnosed with type 1 diabetes, the identification of a KCNJ11 mutation may have important treatment implications. Diabetes 53: 2998 -3001, 2004 W e have recently shown that heterozygous mutations in the Kir6.2 (KCNJ11) gene, on chromosome 11p15.1, accounts for approximately one-third of cases of permanent neonatal diabetes mellitus (PNDM) (1). The gene encodes a subunit of the ␤-cell ATP-sensitive K ϩ channel (K ATP channel) known as the inwardly rectifying K ϩ channel (Kir6.2). The K ATP channel plays a critical role in coupling metabolism to membrane electrical events, which bring about closure of the K ATP channel and initiate insulin secretion. Activating mutations in KCNJ11 cause familial and sporadic PNDM by decreasing ␤-cell insulin secretion through reduced ATP sensitivity of the K ATP channel (1). Subjects presented with marked hyperglycemia and ketoacidosis at a mean age of 7 weeks (range 0 -26), with 15% presenting outside 3 months. We hypothesized that KCNJ11 activating mutations could present in young children with a clinical diagnosis of type 1 diabetes.The KCNJ11 gene, encoding Kir6.2, is located close to the large IDDM2 linkage peak (logarithm of odds [LOD] ϭ 4.28) at 11p15.5 seen in the combined analysis of the U.S. and the U.K. type 1 diabetes genome-wide scans (2). IDDM2 is primarily explained by the insulin gene variable number tandem repeat (INS VNTR) region, located upstream of the insulin gene. However, after allowing for the INS VNTR, the resulting LOD score for chromosome 11 in this region was still suggestive of linkage (LOD ϭ 2.53), and it was suggested by Cox et al. (2) that there could be a second type 1 diabetes locus in this region. A subset of families linked to KCNJ11 might explain this. A recent large study did not find any association with type 1 diabetes of the single nucleotide polymorphism E23K in KCNJ11 (3).Type 1 diabetes is defined by an absolute deficiency of insulin secretion (4). The most common form is immunemedia...

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“…However, they are particularly sensitive to the hypoglycaemic effects of sulphonylureas. 7 The availability of genetic testing to identify mutations in HNF-1 alpha, knowledge of sulphonylurea sensitivity and isolated case reports 2,8 indicate that some HNF-1 alpha patients treated with insulin may benefit from transferring to sulphonylureas.…”

Section: Hnf-1 Alpha Modymentioning

confidence: 99%

‘I'm amazed I've been able to come off injections’: patients' perceptions of genetic testing in diabetes

Shepherd

2003

Pract Diab Int

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Maturity onset diabetes of the young (MODY) accounts for 1% of diabetes in the UK but the young age of diagnosis, high glucose values in slim patients and lack of professionals' familiarity with the family history often lead to a misdiagnosis of type 1 diabetes. The identification of six different genes that cause MODY means that genetic testing may confirm the diagnosis and define the subtype. MODY patients with a mutation in the hepatocyte nuclear factor‐1 alpha (HNF‐1 alpha) gene are known to be particularly sensitive to the hypoglycaemic effect of sulphonylureas which has implications for their treatment. In depth interviews were conducted with 18 HNF‐1 alpha MODY patients, on insulin from diagnosis, who were offered the possibility of transferring to a sulphonylurea. A qualitative approach was used to gain an in depth understanding of their perceptions about stopping insulin. Six key themes emerged: (i) concern and anticipation about the prospect of stopping insulin; (ii) interactions with health care professionals; (iii) the impact on glycaemic control; (iv) improved lifestyle and self‐image; (v) reflections regarding the time on insulin; and (vi) difficulty in ‘letting go’ of insulin treatment. Transferring insulin treated HNF‐1 alpha MODY patients to sulphonylureas was safe in the short term. All 18 patients reported positive lifestyle changes and most showed no deterioration in glycaemic control, although the progressive nature of HNF‐1 alpha MODY means they are likely to need insulin again in the future. These findings have implications for other patients able to stop insulin after many years, such as those undergoing islet cell transplantation. Copyright © 2003 John Wiley & Sons, Ltd.

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Identifying Hepatic Nuclear Factor 1α Mutations in Children and Young Adults With a Clinical Diagnosis of Type 1 Diabetes

Cited by 75 publications

References 22 publications

Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young

Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young

Activating Mutations in the KCNJ11 Gene Encoding the ATP-Sensitive K+ Channel Subunit Kir6.2 Are Rare in Clinically Defined Type 1 Diabetes Diagnosed Before 2 Years

‘I'm amazed I've been able to come off injections’: patients' perceptions of genetic testing in diabetes

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