RGD Reference Report - Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. - Rat Genome Database

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Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene.

Authors: Pearson, Ewan R  Boj, Sylvia F  Steele, Anna M  Barrett, Timothy  Stals, Karen  Shield, Julian P  Ellard, Sian  Ferrer, Jorge  Hattersley, Andrew T 
Citation: Pearson ER, etal., PLoS Med. 2007 Apr;4(4):e118.
RGD ID: 12904698
Pubmed: PMID:17407387   (View Abstract at PubMed)
PMCID: PMC1845156   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pmed.0040118   (Journal Full-text)


BACKGROUND: Macrosomia is associated with considerable neonatal and maternal morbidity. Factors that predict macrosomia are poorly understood. The increased rate of macrosomia in the offspring of pregnant women with diabetes and in congenital hyperinsulinaemia is mediated by increased foetal insulin secretion. We assessed the in utero and neonatal role of two key regulators of pancreatic insulin secretion by studying birthweight and the incidence of neonatal hypoglycaemia in patients with heterozygous mutations in the maturity-onset diabetes of the young (MODY) genes HNF4A (encoding HNF-4alpha) and HNF1A/TCF1 (encoding HNF-1alpha), and the effect of pancreatic deletion of Hnf4a on foetal and neonatal insulin secretion in mice.
METHODS AND FINDINGS: We examined birthweight and hypoglycaemia in 108 patients from families with diabetes due to HNF4A mutations, and 134 patients from families with HNF1A mutations. Birthweight was increased by a median of 790 g in HNF4A-mutation carriers compared to non-mutation family members (p < 0.001); 56% (30/54) of HNF4A-mutation carriers were macrosomic compared with 13% (7/54) of non-mutation family members (p < 0.001). Transient hypoglycaemia was reported in 8/54 infants with heterozygous HNF4A mutations, but was reported in none of 54 non-mutation carriers (p = 0.003). There was documented hyperinsulinaemia in three cases. Birthweight and prevalence of neonatal hypoglycaemia were not increased in HNF1A-mutation carriers. Mice with pancreatic beta-cell deletion of Hnf4a had hyperinsulinaemia in utero and hyperinsulinaemic hypoglycaemia at birth.
CONCLUSIONS: HNF4A mutations are associated with a considerable increase in birthweight and macrosomia, and are a novel cause of neonatal hypoglycaemia. This study establishes a key role for HNF4A in determining foetal birthweight, and uncovers an unanticipated feature of the natural history of HNF4A-deficient diabetes, with hyperinsulinaemia at birth evolving to decreased insulin secretion and diabetes later in life.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HNF4AHumanFetal Macrosomia  IAGP DNA:mutations: :RGD 
Hnf4aRatFetal Macrosomia  ISOHNF4A (Homo sapiens)DNA:mutations: :RGD 
Hnf4aMouseFetal Macrosomia  ISOHNF4A (Homo sapiens)DNA:mutations: :RGD 
HNF4AHumanhyperinsulinism  ISOHnf4a (Mus musculus) RGD 
Hnf4aRathyperinsulinism  ISOHnf4a (Mus musculus) RGD 
Hnf4aMousehyperinsulinism  IMP  RGD 
HNF4AHumanhypoglycemia  ISOHnf4a (Mus musculus) RGD 
Hnf4aRathypoglycemia  ISOHnf4a (Mus musculus) RGD 
Hnf4aMousehypoglycemia  IMP  RGD 

Phenotype Annotations    Click to see Annotation Detail View

Manual Human Phenotype Annotations - RGD

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
HNF4AHumanHypoglycemia  IAGP DNA:mutations: :RGD 
HNF4AHumanLarge for gestational age  IAGP DNA:mutations: :RGD 
Objects Annotated

Genes (Rattus norvegicus)
Hnf4a  (hepatocyte nuclear factor 4, alpha)

Genes (Mus musculus)
Hnf4a  (hepatic nuclear factor 4, alpha)

Genes (Homo sapiens)
HNF4A  (hepatocyte nuclear factor 4 alpha)


Additional Information