MOLECULAR-GENETICS OF FAMILIAL HYPERCHOLESTEROLEMIA IN ISRAEL

Familial hypercholesterolemia (FH) is an autosomal dominant disease ca used by a multitude of low density lipoprotein receptor (LDL-R) mutati ons. The purpose of the current investigation was to define the spectr um of mutations causing FH in Israel and determine their relative dist ribution among diverse origin groups. A total of 193 FH families were recruited in Israel, 54 of them through the MED PED (Make Early Diagno sis Prevent Early Death) FH program. Molecular analysis of the LDL-R u sing single-strand conformation polymorphism (SSCP) or denaturing grad ient gel electrophoresis (DGGE) or both has been completed in 95 index cases. This analysis resulted in the identification of 15 LDL recepto r mutations, including 7 novel mutations (del 197, C308G, R385W, splic e junction mutation of intron 14, del 328, del 502-505, stop 10, del 1 65), that were present in 49 index cases (52%). The 15 mutations are m apped to three known functional domains of the receptor (7 in the LDL- binding region, 7 in the epidermal growth factor precursor homology re gion and 1 in the membrane-spanning region). Screening for the identif ied mutations in the remaining 98 index cases enabled the molecular di agnosis of 31 additional cases. It is therefore concluded that 80 out of 193 index cases (41%) harbor 1 of the 15 mutations described here. Three mutations - del(197) (FH-Lithuania), D147H (FH-Sephardic), and s top(660) (Lebanese allele) - were found in a total of 66 index cases ( 34%); these may be regarded as founder mutations in the three respecti ve origin groups. In conclusion, in Israel molecular heterogeneity at the LDL receptor gene locus reflects the ethnic distribution of its or igin groups. The results of the present investigation provide valuable diagnostic tools for a subset of the Israeli patients with FH who are at high risk for atherosclerosis and its complications.