MUTATIONS IN THE DELTA-7-STEROL REDUCTASE GENE IN PATIENTS WITH THE SMITH-LEMLI-OPITZ-SYNDROME

The Smith-Lemli-Opitz syndrome (SLOS) is an inborn disorder of sterol metabolism with characteristic congenital malformations and dysmorphia s. All patients suffer from mental retardation. Here we identify the S LOS gene as a Delta 7-sterol reductase (DHCR7, EC 1.3.1.21) required f or the de novo biosynthesis of cholesterol, The human and murine genes were characterized and assigned to syntenic regions on chromosomes 11 q13 and 7F5 by fluorescense in situ hybridization, Among the mutations found in patients with the SLOS, are missense (P51S, T93M, L99P, L157 P, A247V, V326L, R352W, C380S, R404C, and G410S), nonsense (W151X), an d splice site (IVS8-1G>C) mutations as well as an out of frame deletio n (720-735 del), The missense mutations L99P, V326L, R352W, R404C, and G410S reduced heterologous protein expression by >90%. Our results st rongly suggest that defects in the DHCR7 gene cause the SLOS.