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.
Savage
David B
DB
Department of Clinical Biochemistry, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK.
Agostini
Maura
M
Barroso
Inês
I
Gurnell
Mark
M
Luan
Jian'an
J
Meirhaeghe
Aline
A
Harding
Anne-Helen
AH
Ihrke
Gudrun
G
Rajanayagam
Odelia
O
Soos
Maria A
MA
George
Stella
S
Berger
Dirk
D
Thomas
E Louise
EL
Bell
Jimmy D
JD
Meeran
Karim
K
Ross
Richard J
RJ
Vidal-Puig
Antonio
A
Wareham
Nicholas J
NJ
O'Rahilly
Stephen
S
Chatterjee
V Krishna K
VK
Schafer
Alan J
AJ
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