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.
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.
Bellanné-Chantelot
Christine
C
Department of Cytogenetics and Molecular Biology, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France. christine.bellanne@sat.ap-hop-paris.fr
Clauin
Séverine
S
Chauveau
Dominique
D
Collin
Philippe
P
Daumont
Michèle
M
Douillard
Claire
C
Dubois-Laforgue
Danièle
D
Dusselier
Laurent
L
Gautier
Jean-François
JF
Jadoul
Michel
M
Laloi-Michelin
Marie
M
Jacquesson
Laetitia
L
Larger
Etienne
E
Louis
Jacques
J
Nicolino
Marc
M
Subra
Jean-François
JF
Wilhem
Jean-Marie
JM
Young
Jacques
J
Velho
Gilberto
G
Timsit
José
J
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
C496495:HNF1B protein, human; D051539:Hepatocyte Nuclear Factor 1-beta