Modifying Factors in Smith-Lemli-Opitz Syndrome

The Smith-Lemli-Opitz syndrome (SLOS, MIM 270400) is an autosomal recessive metabolic disorder of cholesterol biosynthesis resulting in mental retardation, facial dysmorphisms, failure to thrive, and variable malformations including microcephaly, cleft palate, syndactyly of toes 2/3, polydactyly, visceral malformations, variable anomalies of the heart and kidneys, and ambigous genitalia in males. The clinical presentation ranges from mild dysmorphisms with moderate mental impairment to intrauterine death. The frequency of this syndrome was estimated in European populations between 1:15.000 to 1: 40.000. The basic defect of SLOS was found to be in the conversion of 7DHC to cholesterol, the last step of cholesterol synthesis, which is catalyzed by the enzyme delta7- sterol reductase (DHCR7, E.C. 1.3.1.21). Mutations in the DHCR7 gene have been identified in patients with Smith-Lemli-Opitz syndrome. Until now more than 70 mutations have been detected. Some of these including null mutations associated with the most severe phenotype are frequent. Identification of potential modifyer genes of the SLOS phenotype will be attempted by candidate gene approach. Several candidate genes have been chosen because of playing a role in cholesterol transport or in cholesterol function: apolipoprotein E, lipoprotein receptor-related protein (LRP), megalin (gp330), scavenger receptor class B type I, cubulin (gp280), Sonic hedgehog, Patched, and Smoothened. SNPs in these genes will be identified by electronic-PCR, DHPLC or sequencing analysis. Expression studies will show if the found variants are differentially expressed and therefore functional SNPs or anonymous markers. Haplotypes will be determined in trios and families with at least one affected SLOS child. Affected children will be categorized into severe, intermediate, and mild using a scoring system, which was already used for the DHCR7 genotype - SLOS phenotype correlation (Witsch-Baumgartner et al., 2000). By this approach it should be possible to evaluate which factors play a role in the pathogenesis of SLOS. This might give insights into embryonic development, but also in cholesterol homeostasis and related disorders in general (e.g. atherosclerosis, Alzheimer disease).