In silico
            and
            in vitro
            analyses of the pathological relevance of the R258H mutation of hepatocyte nuclear factor 4α identified in maturity‐onset diabetes of the young type 1

Background/Aims: Maturity onset diabetes of the young (MODY) is a rare condition often misdiagnosed as type 1 diabetes (T1D). The purposes of this study were: to identify any patients followed in a large Turkish cohort as T1D, with an atypical natural history, who may in fact have MODY, and to define the criteria which would indicate patients with likely MODY as early as possible after presentation to allow prompt genetic testing. Methods: Urinary C-peptide/creatinine ratio (UCPCR) was studied in 152 patients having a diagnosis of T1D for at least 3 years. Those with a UCPCR ≥0.2 nmol/mmol were selected for genetic analysis of the Glucokinase (GCK), Hepatocyte nuclear factor 1a (HNF1A), Hepatocyte nuclear factor 4a (HNF4A), and Hepatocyte nuclear factor 1b (HNF1B) genes. This UCPCR cut-off was used because of the reported high sensitivity and specificity. Cases were also evaluated using a MODY probability calculator. Results: Twenty-three patients from 152 participants (15.1%) had a UCPCR indicating persistent insulin reserve. The mean age ± SD of the patients was 13.6 ± 3.6 years (range 8.30–21.6). Of these 23, two (8.7%) were found to have a mutation, one with HNF4A and one with HNF1B mutation. No mutations were detected in the GCK or HNF1A genes. Conclusion: In Turkish children with a diagnosis of T1D but who have persistent insulin reserve 3 years after diagnosis, up to 9% may have a genetic mutation indicating a diagnosis of MODY.

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Hepatocyte Nuclear Factor-4 Involved in Type 1 Maturity-Onset Diabetes of the Young Is a Novel Target of AMP-Activated Protein Kinase

Diabetes ◽

10.2337/diabetes.50.7.1515 ◽

2001 ◽

Vol 50 (7) ◽

pp. 1515-1521 ◽

Cited By ~ 100

Author(s):

I. Leclerc ◽

C. Lenzner ◽

L. Gourdon ◽

S. Vaulont ◽

A. Kahn ◽

...

Keyword(s):

Protein Kinase ◽

Nuclear Factor ◽

Maturity Onset Diabetes ◽

Hepatocyte Nuclear Factor ◽

Onset Diabetes ◽

Hepatocyte Nuclear Factor 4 ◽

Novel Target ◽

Amp Activated Protein Kinase

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Maturity-Onset Diabetes of the Young Type 1 (MODY1)-Associated Mutations R154X and E276Q in Hepatocyte Nuclear Factor 4α (HNF4α) Gene Impair Recruitment of p300, a Key Transcriptional Coactivator

Molecular Endocrinology ◽

10.1210/mend.15.7.0670 ◽

2001 ◽

Vol 15 (7) ◽

pp. 1200-1210 ◽

Cited By ~ 1

Author(s):

Jérôme Eeckhoute ◽

Pierre Formstecher ◽

Bernard Laine

Keyword(s):

Transcription Factor ◽

Transcriptional Activity ◽

Cell Function ◽

Nuclear Factor ◽

Maturity Onset Diabetes ◽

Hepatocyte Nuclear Factor ◽

Β Cell ◽

Β Cell Function ◽

Hepatocyte Nuclear Factor 4Α

Abstract Hepatocyte nuclear factor 4α (HNF4α) is a nuclear receptor involved in glucose homeostasis and is required for normal β-cell function. Mutations in the HNF4α gene are associated with maturity-onset diabetes of the young type 1. E276Q and R154X mutations were previously shown to impair intrinsic transcriptional activity (without exogenously supplied coactivators) of HNF4α. Given that transcriptional partners of HNF4α modulate its intrinsic transcriptional activity and play crucial roles in HNF4α function, we investigated the effects of these mutations on potentiation of HNF4α activity by p300, a key coactivator for HNF4α. We show here that loss of HNF4α function by both mutations is increased through impaired physical interaction and functional cooperation between HNF4α and p300. Impairment of p300-mediated potentiation of HNF4α transcriptional activity is of particular importance for the E276Q mutant since its intrinsic transcriptional activity is moderately affected. Together with previous results obtained with chicken ovalbumin upstream promoter-transcription factor II, our results highlight that impairment of recruitment of transcriptional partners represents an important mechanism leading to abnormal HNF4α function resulting from the MODY1 E276Q mutation. The impaired potentiations of HNF4α activity were observed on the promoter of HNF1α, a transcription factor involved in a transcriptional network and required for β-cell function. Given its involvement in a regulatory signaling cascade, loss of HNF4α function may cause reduced β-cell function secondary to defective HNF1α expression. Our results also shed light on a better structure-function relationship of HNF4α and on p300 sequences involved in the interaction with HNF4α.

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