title: Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5.
abstract: Maturity-onset diabetes of the young (MODY) 5 is caused by mutations in the TCF2 gene encoding the transcription factor hepatocyte nuclear factor-1beta. However, in 60% of the patients with a phenotype suggesting MODY5, no point mutation is detected in TCF2. We have hypothesized that large genomic rearrangements of TCF2 that are missed by conventional screening methods may account for this observation. In 40 unrelated patients presenting with MODY5 phenotype, TCF2 was screened for mutations by sequencing. Patients without mutations were then screened for TCF2 rearrangements by the quantitative multiplex PCR of short fluorescent fragments (QMPSF). Among the 40 patients, the overall detection rate was 70%: 18 had point mutations, 9 had whole-gene deletions, and 1 had a deletion of a single exon. Similar phenotypes were observed in patients with mutations and in subjects with large deletions. These results suggest that MODY5 is more prevalent than previously reported, with one-third of the cases resulting from large deletions of TCF2. Because QMPSF is more rapid and cost effective than sequencing, we propose that patients whose phenotype is consistent with MODY5 should be screened first with the QMPSF assay. In addition, other MODY genes should be screened for large genomic rearrangements.
authors.affiliation: Department of Cytogenetics and Molecular Biology, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France. christine.bellanne@sat.ap-hop-paris.fr
authors.forename: Christine
authors.initials: C
authors.lastname: Bellanné-Chantelot
authors.forename: Séverine
authors.initials: S
authors.lastname: Clauin
authors.forename: Dominique
authors.initials: D
authors.lastname: Chauveau
authors.forename: Philippe
authors.initials: P
authors.lastname: Collin
authors.forename: Michèle
authors.initials: M
authors.lastname: Daumont
authors.forename: Claire
authors.initials: C
authors.lastname: Douillard
authors.forename: Danièle
authors.initials: D
authors.lastname: Dubois-Laforgue
authors.forename: Laurent
authors.initials: L
authors.lastname: Dusselier
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Gautier
authors.forename: Michel
authors.initials: M
authors.lastname: Jadoul
authors.forename: Marie
authors.initials: M
authors.lastname: Laloi-Michelin
authors.forename: Laetitia
authors.initials: L
authors.lastname: Jacquesson
authors.forename: Etienne
authors.initials: E
authors.lastname: Larger
authors.forename: Jacques
authors.initials: J
authors.lastname: Louis
authors.forename: Marc
authors.initials: M
authors.lastname: Nicolino
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Subra
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Wilhem
authors.forename: Jacques
authors.initials: J
authors.lastname: Young
authors.forename: Gilberto
authors.initials: G
authors.lastname: Velho
authors.forename: José
authors.initials: J
authors.lastname: Timsit
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000483:Alleles; D001483:Base Sequence; D002874:Chromosome Mapping; D003924:Diabetes Mellitus, Type 2 / Q000145:classification* / Q000235:genetics*; D005260:Female; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010641:Phenotype
chemical_list: C496495:HNF1B protein, human; D051539:Hepatocyte Nuclear Factor 1-beta