Clinical heterogeneity of abnormal glucose homeostasis associated with the HNF4A R311H mutation
© Delvecchio et al.; licensee BioMed Central Ltd. 2014
Received: 24 February 2014
Accepted: 12 June 2014
Published: 19 June 2014
Maturity Onset Diabetes of the Young (MODY; MIM#606391) represents a genetically and clinically heterogeneous form of diabetes mellitus (DM) [1–3], characterized by hyperglycaemia or overt diabetes, in at least two or three consecutive generations, onset <25 years of age, absence of anti ß-cells antibodies. Loss-of-function HNF4A mutations cause a progressive loss of ß-cell function  and, eventually, frank hyperglycaemia denominated as MODY1. HNF4A mutations have been associated with MODY1, type 2 diabetes and gestational diabetes (GDM) .
The table shows clinical and biochemistry data of the proband at DM diagnosis in the upper part and data at last examination of all mutation carriers (including proband) in the lower part
Proband’s data at the time of clinical diagnosis of DM (i.e. at age of 9.1 years)
Total/HDL cholesterol (mg/dl)
176 / 34
Systolic/diastolic blood pressure (mmHg)
113 / 65
Anti-thyroid, ICA, GAD, IA-2 antigens antibodies
Oral glucose tolerance test
Blood glucose (mg/dl)
Blood insulin (microU/ml)
Before glucose load
30 min after glucose load
60 min after glucose load
90 min after glucose load
120 min after glucose load
Age at examination (yrs)
Age at diagnosis (yrs)
Glycaemic status diagnosed
Age at genetic testing (yrs)
BMI (Kg/m 2 )
Blood pressure (mmHg)
107 / 68
110 / 60
160 / 90
130 / 80
Fasting blood glucose (mg/dl)
Total cholesterol (mg/dl)
HDL cholesterol (mg/dl)
LDL cholesterol (mg/dl)
Diet, physical activity
Diet, physical activity
At admission, two IU of regular insulin at lunch and at dinner and a hypocaloric diet (BMI 24.1 kg/m2, 95th centile) were started. Three weeks later, body weight had dropped 1 kg and insulin injections were stopped because of recurrent hypoglycaemias. The patient was referred to our Unit 5 months later, still off of insulin. At that time, HbA1c was 40 mmol/mol and BMI 19.4 kg/m2 (75th centile). The HNF4A (NM_175914.4) gene analysis by PCR followed by direct sequencing showed the p.R311H c.932G > A variation in exon 8 (previously reported as p.R323H ). This mutation resides in the highly conserved extreme carboxy terminal domain  and causes a semiconservative aminoacid substitution predicted to be probably damaging by The Human Gene Mutation Database (http://www.hgmd.org)  and by PolyPhen-2 tool . Genetic analysis was carried out also in first-degree relatives and in the maternal uncles, showing the same mutation in the mother, the brother, and the diabetic uncle. They underwent a comprehensive laboratory evaluation (Table 1). When 7.9 year-old, the brother underwent further examination showing impaired glucose tolerance (IGT) (baseline and after 120′ blood glucose and insulin: 78 and 151 mg/dl, 6.4 and 58.7 ng/ml, respectively), low insulin production (Matsuda Index 28.56, HOMA-IR 0.77, Insulinogenic Index −0.05, Disposition Index 0), HbA1c 39 mmol/mol, and BMI 20.4 kg/m2 (90th centile).
HNF4A mutations lead to a progressive decrease of insulin secretion and hyperglycaemia  requiring oral hypoglycaemic drugs or insulin in most cases . Our proband required low insulin dose (0.09 IU/kg/day) only for few weeks. This transient course is puzzling and never described in HNF4A- MODY children so far. Likely, in the weeks before the diagnosis, some triggering factors played a role in deteriorating glucose homeostasis. As she became normoglycaemic and insulin free after some weight lost, we suggest that overweight may have played a major role, but we cannot exclude the role of other concomitant factors (stress or infectious diseases). Currently the proband, 11-year-old, is on normocaloric diet and presents a good glycaemic control (HbA1c 40 mmol/mol) without any hypoglycaemic treatment.
We did not perform any molecular study showing the effect of the mutation, so no direct effect can be postulated. However, we show that it segregates with hyperglycaemia, as it was found in the mother (GDM, currently normoglycaemic and normal weight), in the maternal uncle (type 2 DM onset at 30 years of age, currently overweight, diabetic and on hypoglycaemic diet), and in the brother (IGT). The same mutation was previously described in a 46 year-old obese man with type 2 DM and nephropathy . Later, in the same position, a mutation with Arginine replaced by Cysteine (previously reported as p.R324C), was described in a 13 year-old Japanese MODY patient . Unfortunately, no information about the families were reported in both cases, making impossible to speculate about any role of HNF4A-R311H on glucose homeostasis. To better assess its pathogenic role, we screened 198 non-diabetic individuals and 138 type 2 DM patients without family history of autosomal dominant inheritance of hyperglycaemia / diabetes and negative data were obtained.
The in silico analysis suggests that the R311H mutation causes a semiconservative aminoacid substitution predicted to be probably damaging [10, 11]. Since some studies indicates a neutral , and others a deleterious  effect of such variation on HNF4A transcriptional activity, its biological role is controversial.
In conclusion, we report on a family with the HNF4A-R311H mutation cosegregating with heterogeneous phenotype of abnormal glucose homeostasis, including MODY1. The lack of a clear genotype-phenotype association requires great caution before considering this mutation causative of MODY1. We suggest that also transient DM warrants the screening for MODY in the presence of indicative family history, even if with clinical heterogeneity of abnormal glucose homeostasis.
Informed consent was obtained from the patient's parents for publication of this case report.
Impaired glucose tolerance
Oral glucose tolerance test
Gestational diabetes mellitus.
The study was partially supported by Italian Ministry of Health grant RC2013 to MS.
- Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S: Maturity-onset diabetes of the young (MODY): how many cases are we missing?. Diabetologia. 2012, 53: 2504-2508.View ArticleGoogle Scholar
- Fajans SS, Bell GI, Polonsky KS: Molecular mechanisms and clinical pathophysiology of maturity-onset diabetes of the young. N Engl J Med. 2001, 345: 971-980.View ArticlePubMedGoogle Scholar
- Schober E, Rami B, Grabert M, Thon A, Kapellen T, Reinehr T, Holl RW, DPV-Wiss Initiative of the German Working Group for Paediatric Diabetology: Phenotypical aspects of maturity-onset diabetes of the young (MODY diabetes) in comparison with Type 2 diabetes mellitus (T2DM) in children and adolescents: experience from a large multicentre database. Diabet Med. 2009, 26: 466-473.View ArticlePubMedGoogle Scholar
- Herman WH, Fajans SS, Smith MJ, Polonsky KS, Bell GI, Halter JB: Diminished insulin and glucagon secretory responses to arginine in nondiabetic subjects with a mutation in the hepatocyte nuclear factor-4alpha/MODY1 gene. Diabetes. 1997, 46 (11): 1749-1754.View ArticlePubMedGoogle Scholar
- Watanabe RM, Black MH, Xiang AH, Allayee H, Lawrence JM, Buchanan TA: Genetics of gestational diabetes mellitus and type 2 diabetes. Diabetes Care. 2007, 30 (2): S134-140. Review. Erratum in: Diabetes Care 2007, 30(12):3154PubMed CentralView ArticlePubMedGoogle Scholar
- Delvecchio M, Ludovico O, Bellacchio E, Stallone R, Palladino T, Mastroianno S, Zelante L, Sacco M, Trischitta V, Carella M: MODY type 2 P59S GCK mutant: founder effect in South of Italy. Clin Genet. 2013, 83: 83-87.View ArticlePubMedGoogle Scholar
- Pearson ER, Boj SF, Steele AM, Barrett T, Stals K, Shield JP, Ellard S, Ferrer J, Hattersley AT: Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007, 4 (4): e118-PubMed CentralView ArticlePubMedGoogle Scholar
- Price JA, Fossey SC, Sale MM, Brewer CS, Freedman BI, Wuerth JP, Bowden DW: Analysis of the HNF4 alpha gene in Caucasian type II diabetic nephropathic patients. Diabetologia. 2000, 43 (3): 364-372.View ArticlePubMedGoogle Scholar
- Ryffel GU: Mutations in the human genes encoding the transcription factors of the hepatocyte nuclearfactor (HNF)1 and HNF4 families: functional and pathological consequences. J Mol Endocrinol. 2001, 27 (1): 11-29.View ArticlePubMedGoogle Scholar
- Stenson PD, Mort M, Ball EV, Shaw K, Phillips AD, Cooper DN: The human gene mutation database (HGMD®): 2008 update. Genome Med. 2008, 1 (1): 13-View ArticleGoogle Scholar
- Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR: A method and server for predicting damaging missense mutations. Nat Methods. 2010, 7 (4): 248-249.PubMed CentralView ArticlePubMedGoogle Scholar
- Gupta RK, Vatamaniuk MZ, Lee CS, Flaschen RC, Fulmer JT, Matschinsky FM, Duncan SA, Kaestner KH: The MODY1 gene HNF-4alpha regulates selected genes involved in insulin secretion. J Clin Invest. 2005, 115 (4): 1006-1015.PubMed CentralView ArticlePubMedGoogle Scholar
- Pearson ER, Pruhova S, Tack CJ, Johansen A, Castleden HA, Lumb PJ, Wierzbicki AS, Clark PM, Lebl J, Pedersen O, Ellard S, Hansen T, Hattersley AT: Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4a mutations in a large European collection. Diabetologia. 2005, 48: 878-885.View ArticlePubMedGoogle Scholar
- Yorifuji T, Fujimaru R, Hosokawa Y, Tamagawa N, Shiozaki M, Aizu K, Jinno K, Maruo Y, Nagasaka H, Tajima T, Kobayashi K, Urakami T: Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus. Pediatr Diabetes. 2012, 13: 26-32.View ArticlePubMedGoogle Scholar
- Oxombre B, Moerman E, Eeckhoute J, Formstecher P, Laine B: Mutations in hepatocyte nuclear factor 4alpha (HNF4alpha) gene associated with diabetes result in greater loss of HNF4alpha function in pancreatic beta-cells than in nonpancreatic beta-cells and in reduced activation of the apolipoprotein CIII promoter in hepatic cells. J Mol Med (Berl). 2002, 80 (7): 423-430.View ArticleGoogle Scholar
- Chandra V, Huang P, Potluri N, Wu D, Kim Y, Rastinejad F: Multidomain integration in the structure of the HNF-4α nuclear receptor complex. Nature. 2013, 495 (7441): 394-398.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.