Analyses of genetic abnormalities in type ICD36 deficiency in Japan: identification and cell biological characterization of two novel mutations that cause CD36 deficiency in man

To elucidate genetic abnormalities in type I CD36 deficiency, we analyzed 2 8 Japanese subjects whose platelets and monocytes/macrophages lacked CD36 o n their surface. We identified two novel mutations in the CD36 gene. One wa s a complex deletion/insertion mutation, in which 3 bp, GAG, were deleted a t nucleotide (nt) 839-841, and 5 bp, AAAAC, were inserted at the same posit ion (839-841del --> insAAAAC). Mutation 839-841del --> insAAAAC led to a fr ameshift and appearance of a premature stop codon; it was also accompanied with a marked reduction in the amount of CD36 mRNA. The other was a 12-bp d eletion at nt 1438-1449 (1438-1449del) accompanied with or without skipping of exon 9 (nt 959-1028). Mutation 1438-1449del led to an inframe 4-amino-a cid deletion, whereas exon 9 skipping led to a frameshift and the appearanc e of a premature stop codon. Expression assay revealed that both 1438-1449d el and exon 9 skipping directly caused impairment of the surface expression of CD36. A survey of the five known mutations including 839-841del --> ins AAAAC and 1438-1449del in type I C1336-deficient subjects demonstrated that the five mutations covered more than 90% of genetic defects among them and that the substitution of T for C at nt 478 (478C -->T) was the most common mutation with more than 50% frequency. However, none of the four subjects that possessed isoantibodies against CD36 had 478C -->T, suggesting that 47 8C -->T prevents the production of isoantibodies against CD36.