Abstract
The aim of this study was characterization of a family carrying two mutations known to cause monogenic forms of diabetes, the M626K mutation in the HNF1alpha gene (MODY3) and the A3243G in mtDNA. Beta-cell function and insulin sensitivity were assessed with the Botnia clamp. Heteroplasmy of the A3243G mutation and variants in type 2 diabetes susceptibility genes were determined, and transcriptional activity, DNA binding, and subcellular localization of mutated HNF1alpha were studied. Thirteen family members carried the mutation in mtDNA; 6 of them also had the M626K mutation, whereas none had only the M626K mutation. The protective Ala12 allele in peroxisome proliferator-activated receptor (PPAR)gamma was present in two nondiabetic individuals. Carriers of both mtDNA and HNF1alpha mutations showed an earlier age at onset of diabetes than carriers of only the mtDNA mutation (median 22 vs. 45 years) but no clear difference in beta-cell function or insulin sensitivity. In vitro, the M626K mutation caused a 53% decrease in transcriptional activity in HeLa cells. The mutated protein showed normal nuclear targeting but increased DNA binding. These data demonstrate that several genetic factors might contribute to diabetes risk, even i...Continue Reading
References
Jul 1, 1977·Diabetes·O K Faber, C Binder
Mar 1, 1990·Genes & Development·S BaumhueterG R Crabtree
Jun 29, 1990·Cell·A NicosiaR Cortese
Sep 20, 1989·Journal of Molecular Biology·S VaulontM Raymondjean
Sep 7, 1995·The New England Journal of Medicine·D R Johns
Jun 1, 1994·Diabetes·J M van den OuwelandJ A Maassen
May 1, 1993·Diabetes·J TakedaG I Bell
Jun 1, 1993·Molecular and Cellular Biology·A A BegA S Baldwin
Feb 23, 1996·Cell·M PontoglioM Yaniv
Jan 1, 1996·Human Mutation·L M 't HartJ A Maassen
Dec 5, 1996·Nature·K YamagataG I Bell
Apr 30, 1998·Diabetologia·B IsomaaL Groop
Aug 1, 1998·Diabetic Medicine : a Journal of the British Diabetic Association·K G Alberti, P Z Zimmet
Aug 14, 1999·Diabetologia·M LehtoL Groop
Nov 3, 2000·Human Mutation·S Ellard
May 1, 2001·Annals of Internal Medicine·P J GuillausseauB Vialettes
Feb 13, 2002·European Journal of Human Genetics : EJHG·C OlssonM Lagerström-Fermér
Jul 13, 2002·American Journal of Medical Genetics·J Antonie Maassen
Jul 30, 2002·Diabetes·Marju Orho-MelanderLeif Groop
Dec 19, 2002·Diabetologia·C CervinC M Cilio
Dec 19, 2002·Diabetologia·T IkemaN Takasu
Apr 30, 2003·Diabetes Care·Devjit TripathyLeif Groop
Jan 30, 2004·Diabetes·J Antonie MaassenHerman H P J Lemkes
Citations
Mar 26, 2011·Acta Diabetologica·Maciej BorowiecWojciech Mlynarski
Sep 8, 2005·Rejuvenation Research·Rafal M Smigrodzki, Shaharyar M Khan
Jan 8, 2016·Human Molecular Genetics·Ian J WilsonPatrick F Chinnery
Apr 29, 2005·Diabetes/metabolism Research and Reviews
Aug 14, 2010·Diabetes Care·Gabriele ForlaniVilma Mantovani
Apr 19, 2007·The Journal of Clinical Endocrinology and Metabolism·Ravi P SahuEesh Bhatia