A genome-wide scan in families with maturity-onset diabetes of the young: evidence for further genetic heterogeneity.
Maturity-onset diabetes of the young (MODY) is a heterogeneous single gene disorder characterized by non-insulin-dependent diabetes, an early onset and autosomal dominant inheritance. Mutations in six genes have been shown to cause MODY. Approximately 15-20% of families fitting MODY criteria do not have mutations in any of the known genes. These families provide a rich resource for the identification of new MODY genes. This will potentially enable further dissection of clinical heterogeneity and bring new insights into mechanisms of beta-cell dysfunction. To facilitate the identification of novel MODY loci, we combined the results from three genome-wide scans on a total of 23 families fitting MODY criteria. We used both a strict parametric model of inheritance with heterogeneity and a model-free analysis. We did not identify any single novel locus but provided putative evidence for linkage to chromosomes 6 (nonparametric linkage [NPL]score 2.12 at 71 cM) and 10 (NPL score 1.88 at 169-175 cM), and to chromosomes 3 (heterogeneity LOD [HLOD] score 1.27 at 124 cM) and 5 (HLOD score 1.22 at 175 cM) in 14 more strictly defined families. Our results provide evidence for further heterogeneity in MODY.
Frayling
Timothy M
TM
Department of Diabetes and Vascular Medicine, Postgraduate School of Medicine and Health Science, University of Exeter, Exeter, U.K.
Lindgren
Cecilia M
CM
Chevre
Jean Claude
JC
Menzel
Stephan
S
Wishart
Marie
M
Benmezroua
Yamina
Y
Brown
Alison
A
Evans
Julie C
JC
Rao
Pamidghantam Subba
PS
Dina
Christian
C
Lecoeur
Cécile
C
Kanninen
Timo
T
Almgren
Peter
P
Bulman
Michael P
MP
Wang
Youxiang
Y
Mills
James
J
Wright-Pascoe
Rosemarie
R
Mahtani
Melanie M
MM
Prisco
Francesco
F
Costa
Angels
A
Cognet
Ignacio
I
Hansen
Torben
T
Pedersen
Oluf
O
Ellard
Sian
S
Tuomi
Tiinamaija
T
Groop
Leif C
LC
Froguel
Philippe
P
Hattersley
Andrew T
AT
Vaxillaire
Martine
M
D000293:Adolescent; D000328:Adult; D002648:Child; D002879:Chromosomes, Human, Pair 10; D002893:Chromosomes, Human, Pair 3; D002895:Chromosomes, Human, Pair 5; D002896:Chromosomes, Human, Pair 6; D004268:DNA-Binding Proteins; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D005838:Genotype; D005941:Glucokinase / Q000235:genetics; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D009154:Mutation; D009687:Nuclear Proteins; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics
D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D005941:Glucokinase