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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 beta-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-4alpha (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 beta-cell.

Type

Journal article

Journal

Diabetes

Publication Date

07/2002

Volume

51

Pages

2329 - 2333

Keywords

Adolescent, Adult, Age Factors, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, Chromosome Mapping, Chromosomes, Human, Pair 20, DNA-Binding Proteins, Diabetes Mellitus, Type 2, Female, Hepatocyte Nuclear Factor 4, Humans, Insulin, Karyotyping, Pedigree, Phosphoproteins, Polymerase Chain Reaction, Receptors, Cytoplasmic and Nuclear, Transcription Factors, Translocation, Genetic