Endocrine Abstracts (2002) 3 OC27

A digenic basis for severe insulin resistance in a large UK kindred - cosegregation of mutations in PPAR gamma and PPP1R3

M Gurnell1, DB Savage1, M Agostini1, I Barroso2, O Rajanayagam1, M Soos1, R Ross3, A Schafer2, S O'Rahilly1 & VKK Chatterjee1

1Department of Medicine, University of Cambridge, Cambridge, UK; 2Incyte Genomics, Cambridge, UK; 3Department of Medicine, Northern General Hospital, Sheffield, UK.

We have previously reported dominant negative missense mutations (P467L, V290M) in human PPAR gamma (peroxisome proliferator-activated receptor gamma) in association with severe insulin resistance, early onset type 2 diabetes and hypertension. In a large UK kindred, where the proband presented at age 15 years with severe insulin resistance (acanthosis nigricans, hyperinsulinaemia, PCOS), we have identified a novel heterozygous frameshift premature stop mutation in the PPAR gamma gene, leading to a mutant receptor which is truncated within the DNA-binding domain. Functional studies indicate that the truncation mutant is unable to transactivate a PPAR gamma target gene, as a consequence of its inability to bind to DNA with its heterodimeric partner RXR. However, unlike the P467L and V290M PPAR gamma mutants, the truncated mutant receptor does not inhibit wild type PPAR gamma action in a dominant negative manner. Heterozygous PPAR gamma null mice retain insulin sensitivity and two individuals in our kindred who harbour the PPAR gamma mutation lack insulin resistance, arguing against haploinsufficiency mediating this phenotype.

We therefore sought additional genetic factor(s) that might contribute to insulin resistance in our kindred. Analyses of other candidate genes led to the identification of a novel frameshift mutation in a skeletal muscle specific isoform of the glycogen targeting subunit of protein phosphatase-1 (PPP1R3). This mutation leads to a prematurely truncated protein with loss of the putative sarcoplasmic reticulum binding domain. When expressed in CHO cells, the mutant protein fails to target appropriately to intracellular membranes - a defect which is likely to alter glycogen synthesis, a key element in insulin-stimulated glucose disposal. Whilst individuals with either the PPAR gamma (n=3) or PPP1R3 (n=2) gene defects alone exhibit normal insulin sensitivity, double heterozygosity for both genetic abnormalities (n=5) cosegregates completely with severe insulin resistance, representing the first description of a digenic form of this disorder.

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