Molecular basis of the Cd36 chromosomal deletion underlying SHR defects in insulin action and fatty acid metabolism.
The human insulin resistance syndromes---type 2 diabetes, obesity, combined hyperlipidemia, and essential hypertension---are genetically complex disorders whose molecular basis is largely unknown. The spontaneously hypertensive rate (SHR) is a model of these human syndromes. In the SHR/NCrlBR strain, a chromosomal deletion event that occurred at the Cd36 locus during the evolution of this SHR strain has been proposed as a cause of defective insulin action and fatty acid metabolism. In this study, three copies of the Cd36 gene, one transcribed copy and two pseudogenes, were identified in normal rat strains, but only a single gene in SHR/NCrlBR. Analysis of SHR genomic sequence localized the chromosomal deletion event between intron 4 of the normally transcribed copy of the gene and intron 4 of the second pseudogene. The deletion led to the creation of a single chimeric Cd36 gene in SHR/NCrlBR. The boundaries of the recombination/deletion junction identified within intron 4 were surrounded by long interspersed nuclear elements (LINEs) and DNA topoisomerase I recognition sequences. An 8-bp deletion at the intron 14/exon 15 boundary of the second pseudogene abolishes the putative splice acceptor site and is the cause of an aberrant 3' UTR previously observed in SHR/NCrlBR. We conclude that in SHR/NCrlBR, the complex trait of insulin resistance and defective fatty acid metabolism is caused by Cd36 deficiency, resulting from a chromosomal deletion caused by unequal recombination. This demonstrates that chromosomal deletions caused by unequal recombination can be a cause of quantitative or complex mammalian phenotypes.
Glazier
Anne M
AM
Physiological Genomics and Medicine Group, MRC Clinical Sciences Centre, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK. anne-marie.glazer@csc.mrc.ac.uk
Scott
James
J
Aitman
Timothy J
TJ
D000818:Animals; D001483:Base Sequence; D018955:CD36 Antigens; D005227:Fatty Acids / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D006973:Hypertension / Q000235:genetics* / Q000378:metabolism*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics*; D008969:Molecular Sequence Data; D027361:Organic Anion Transporters / Q000235:genetics*; D051381:Rats; D011918:Rats, Inbred SHR / Q000235:genetics* / Q000378:metabolism
D018955:CD36 Antigens; D005227:Fatty Acids; D007328:Insulin; D008562:Membrane Glycoproteins; D027361:Organic Anion Transporters