title: Digenic heterozygous HNF1A and HNF4A mutations in two siblings with childhood-onset diabetes.
abstract: Monogenic diabetes due to mutations in the transcription factor genes hepatocyte nuclear factor 1A (HNF1A) and HNF4A is characterized by islet cell antibody negative, familial diabetes with residual insulin secretion. We report two sisters with childhood onset diabetes who are both heterozygous for the most common mutation in each of two transcription factors, HNF1A, and HNF4A. The proband was diagnosed with diabetes at 7 yr of age and treated with insulin for 4 yr. Her genetic diagnosis resulted in transition to sulfonylureas for one and a half years before insulin therapy was re-initiated due to declining glycemic control. Her sister was diagnosed with diabetes at 14 yr of age, treated initially with insulin but has been well controlled on oral sulfonylurea therapy for over 2 yr. Both sisters inherited the HNF4A gene mutation R127W from their mother and the HNF1A gene mutation P291fsinsC (c.872dup) from their father. The father was diagnosed with diabetes at 45 yr of age. Their brother is heterozygous for the HNF4A R127W mutation. Both the brother and mother have normal glucose tolerance at the ages of 16 and 46 yr, respectively. Digenic inheritance of HNF1A and HNF4A mutations is very rare and has only been reported in two families where conclusive evidence for the pathogenicity of their mutations was lacking. Follow-up studies in this family co-segregating the two most commonly reported HNF1A/HNF4A mutations will be informative for understanding the effect of digenic inheritance upon phenotypic severity and response to sulfonylurea therapy.
authors.affiliation: Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Roopa Kanakatti
authors.initials: RK
authors.lastname: Shankar
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
authors.forename: Debra
authors.initials: D
authors.lastname: Standiford
authors.forename: Catherine
authors.initials: C
authors.lastname: Pihoker
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Gilliam
authors.forename: Andrew
authors.initials: A
authors.lastname: Hattersley
authors.forename: Lawrence M
authors.initials: LM
authors.lastname: Dolan
mesh_terms: D000293:Adolescent; D001786:Blood Glucose / Q000378:metabolism; D002648:Child; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D035781:Siblings; D013453:Sulfonylurea Compounds / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; C496487:HNF1A protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D013453:Sulfonylurea Compounds
keywords: HNF1A; HNF4A; MODY; youth
references.citation: Nucleic Acids Res. 2000 Jan 15;28(2):430-7
references.pmid: 10606640
references.citation: N Engl J Med. 2001 Sep 27;345(13):971-80
references.pmid: 11575290
references.citation: Diabetologia. 2000 Apr;43(4):520-4
references.pmid: 10819248
references.citation: Diabetes. 2010 Jan;59(1):266-71
references.pmid: 19794065
references.citation: Hum Mutat. 2006 Sep;27(9):854-69
references.pmid: 16917892
references.citation: Eur J Endocrinol. 2010 May;162(5):987-92
references.pmid: 20164212
references.citation: Diabetes. 1997 Oct;46(10):1652-7
references.pmid: 9313765
references.citation: Diabetes. 2008 Feb;57(2):503-8
references.pmid: 18003757
references.citation: Pediatr Diabetes. 2009 Sep;10 Suppl 12:33-42
references.pmid: 19754616
references.citation: Diabetes. 1999 Jul;48(7):1459-65
references.pmid: 10389854
references.citation: Diabetes Care. 2002 Dec;25(12):2287-91
references.pmid: 12453975
references.citation: Diabetes Care. 2010 Nov;33(11):2336-8
references.pmid: 20705777
references.citation: Diabet Med. 2009 Apr;26(4):437-41
references.pmid: 19388975
references.citation: Diabetologia. 2005 May;48(5):878-85
references.pmid: 15830177
references.citation: Diabet Med. 2009 Nov;26(11):1172-4
references.pmid: 19929997