title: Phenotype of a patient with a de novo mutation in the hepatocyte nuclear factor 1beta/maturity-onset diabetes of the young type 5 gene.
abstract: Mutations in the gene encoding the transcription factor hepatocyte nuclear factor (HNF) 1beta cause various phenotypes including maturity-onset diabetes of the young type 5 (MODY5) and kidney disease. We provide molecular and pathophysiologic characterization of a 23-year-old male patient with clinical presentation typical for MODY5 with renal involvement. Clinical studies (including intravenous glucose tolerance test and magnetic resonance imaging) of the patient and 5 family members in comparison with unrelated control subjects and molecular analysis of the HNF-1beta gene (direct sequencing, paternity testing, and restriction fragment length polymorphism analysis for parental mosaicism) were performed. The patient was born with low birth weight (2250 g), whereas his dizygotic twin sister was of normal weight (3500 g) and healthy. He had cystic renal dysplasia with progressive renal failure and pancreas atrophy with beta-cell dysfunction and early-onset diabetes mellitus but no family history of diabetes. Intravenous glucose tolerance test showed a markedly reduced but not absent acute insulin response compared with controls (n = 6). A mutation in the HNF-1beta gene S148L (C443T) in exon 2 within the pseudo-POU domain was identified. All other family members and the control group (n = 255) did not have the mutation, suggesting that we described a de novo mutation in HNF-1beta. Paternity was confirmed, and no signs of mosaicism in DNA analysis of both parents could be detected. Of note, the low birth weight of the patient in contrast to his healthy twin sister provides interesting support for the fetal insulin hypothesis for reduced birth weight.
authors.affiliation: University of Leipzig, Department of Internal Medicine III, 04103 Leipzig, Germany.
authors.forename: Christof
authors.initials: C
authors.lastname: Mayer
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Böttcher
authors.forename: Peter
authors.initials: P
authors.lastname: Kovacs
authors.forename: Jan
authors.initials: J
authors.lastname: Halbritter
authors.forename: Michael
authors.initials: M
authors.lastname: Stumvoll
mesh_terms: D000328:Adult; D001724:Birth Weight / Q000502:physiology; D002096:C-Peptide / Q000097:blood; D004247:DNA / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005951:Glucose Tolerance Test; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D006801:Humans; D007230:Infant, Low Birth Weight / Q000502:physiology; D007231:Infant, Newborn; D007328:Insulin / Q000097:blood; D007668:Kidney / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009154:Mutation; D010334:Paternity; D010375:Pedigree; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002096:C-Peptide; C496495:HNF1B protein, human; D007328:Insulin; D051539:Hepatocyte Nuclear Factor 1-beta; D004247:DNA