Maturity-Onset Diabetes of the Young Caused by a Balanced Translocation Where the 20q12 Break Point Results in Disruption Upstream of the Coding Region of Hepatocyte Nuclear Factor-4α (HNF4A) Gene
- Anna L. Gloyn1,
- Sian Ellard1,
- Maggie Shepherd1,
- Rodney T. Howell2,
- Elizabeth M. Parry3,
- Andrew Jefferson4,
- Elaine R. Levy4 and
- Andrew T. Hattersley1
- 1Department of Diabetes and Vascular Medicine, University of Exeter, Exeter, U.K.
- 2Regional Cytogenetics Centre, Southmead Hospital, Bristol, U.K.
- 3School of Biological Sciences, University of Wales, Swansea, U.K.
- 4Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K.
Abstract
Monogenic human disorders have been used as paradigms for complex genetic disease and as tools for establishing important insights into mechanisms of gene regulation and transcriptional control. Maturity-onset diabetes of the young (MODY) is a monogenic dominantly inherited form of diabetes that is characterized by defective insulin secretion from the pancreatic β-cells. A wide variety of mutation types in five different genes have been identified that result in this condition. There have been no reports of a chromosome deletion or translocation resulting in MODY. We report a pedigree where MODY cosegregates with a balanced translocation [karyotype 46, XX t(3;20) (p21.2;q12)]. The chromosome 20 break point, 20q12, is within the region of one of the known MODY genes, hepatocyte nuclear factor-4α (HNF4A). Fluorescence in situ hybridization analysis demonstrated that the break point does not disrupt the coding region of this gene, but it lies at least 6 kb upstream of the conventional promoter (P1). We propose that this mutation disrupts the spatial relationship between the recently described alternate distal pancreatic promoter (P2) and HNF4A. This is the first case of MODY due to a balanced translocation, and it provides evidence to confirm the crucial role of an upstream regulator of HNF4A gene expression in the β-cell.
Footnotes
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Address correspondence and reprint requests to Professor Andrew T. Hattersley, Department of Vascular Medicine and Diabetes Research, School of Postgraduate Medical and Health Sciences, Barrack Road, Exeter, EX2 5AX, U.K. E-mail a.t.hattersley{at}exeter.ac.uk.
Received for publication 19 December 2001 and accepted in revised form 9 April 2002.
apo, apolipoprotein; DAPI, 4′,6′-diamidino-2-phenylindole; DIG, digozigenin; FISH, fluorescence in situ hybridization; FITC, fluorescein isiothiocyanate; HNF, hepatocyte nuclear factor; HOMA, homeostasis model assessment; IPF, insulin promoter factor; MODY, maturity-onset diabetes of the young; SSC, sodium chloride-sodium citrate.
- DIABETES
