Mutational Analysis of the Estrogen Receptor Alpha Gene in Israeli Osteoporotic Men and Women

Genetic factors play a pivotal role in the predisposition to osteoporosis. SevERαl lines of evidence implicate the estrogen receptor alpha (ERα) gene as a contributor to osteoporosis, but the existence of germline mutations in osteoporotic patients has not been systematically evaluated. We performed germline mutation analysis of the ERα gene in 38 Israeli premenopausal osteoporotic women and 48 osteoporotic men. All coding exons of the ERα gene were PCR amplified, analyzed by denaturing gradient gel electrophoresis, and complemented by DNA sequencing. Four previously published neutral polymorphisms were detected: TCT→TCC in codon 10 (serine) (9/39 [23%] of men, and 6/36 [16.6%] of women); ACA→ACG in codon 311 (threonine) in a single woman; CCC→CCG in codon 325 (proline) (4/46 [8.7%] of men, and 1/38 [2.6%] of women); ACA→ACG in codon 594 (threonine) (4/41 [9.7%] of men and 3/32 [9.4%] of women). In one osteoporotic woman, a G to A change at position cl067 resulting in CGA (arginine) at codon 259 resulting in a stop codon (R259X) was noted. We conclude that ERα gene mutations are only rarely involved in osteoporosis in Jewish Israeli men and premenopausal women. KEY WORDS denaturing gradient gel electrophoresis (DGGE), estrogen receptor, inactivating mutation, polymorphisms, osteoporosis.