Digenic inheritance of severe insulin resistance in a human pedigree.
Impaired insulin action is a key feature of type 2 diabetes and is also found, to a more extreme degree, in familial syndromes of insulin resistance. Although inherited susceptibility to insulin resistance may involve the interplay of several genetic loci, no clear examples of interactions among genes have yet been reported. Here we describe a family in which five individuals with severe insulin resistance, but no unaffected family members, were doubly [corrected] heterozygous with respect to frameshift/premature stop mutations in two unlinked genes, PPARG and PPP1R3A these encode peroxisome proliferator activated receptor gamma, which is highly expressed in adipocytes, and protein phosphatase 1, regulatory subunit 3, the muscle-specific regulatory subunit of protein phosphatase 1, which are centrally involved in the regulation of carbohydrate and lipid metabolism, respectively. That mutant molecules primarily involved in either carbohydrate or lipid metabolism can combine to produce a phenotype of extreme insulin resistance provides a model of interactions among genes that may underlie common human metabolic disorders such as type 2 diabetes.
Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
David B
DB
Savage
Maura
M
Agostini
Inês
I
Barroso
Mark
M
Gurnell
Jian'an
J
Luan
Aline
A
Meirhaeghe
Anne-Helen
AH
Harding
Gudrun
G
Ihrke
Odelia
O
Rajanayagam
Maria A
MA
Soos
Stella
S
George
Dirk
D
Berger
E Louise
EL
Thomas
Jimmy D
JD
Bell
Karim
K
Meeran
Richard J
RJ
Ross
Antonio
A
Vidal-Puig
Nicholas J
NJ
Wareham
Stephen
S
O'Rahilly
V Krishna K
VK
Chatterjee
Alan J
AJ
Schafer
D000328:Adult; D000368:Aged; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D006579:Heterozygote; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000378:metabolism; D054645:Protein Phosphatase 1; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D004268:DNA-Binding Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D014157:Transcription Factors; C114205:PPP1R3A protein, human; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1