What Is Known About The Underlying Genetic Cause of Smith Lemli Opitz Syndrome?
Molecular geneticists have determined that SLOS is inherited in an autosomal recessive manner and is caused by mutations present in a single gene designated DHCR7, otherwise known as the 7-dehydrocholesterol reductase gene. Normal, or non-mutant, versions of the DHCR7 gene encode the protein 7-dehydrocholesterol reductase necessary for proper synthesis of cholesterol in certain cells.
Mutant versions of the DHCR7 gene either do not yield any 7-dehydrocholesterol reductase or they yield a defective form of 7-dehydrocholesterol reductase. In either event, this means that cholesterol is not made. This is problematic because cholesterol that is normally synthesized by our bodies is necessary for proper fetal development. Specifically, it is involved in many required interactions with various proteins that regulate early development of several organs, including the brain, the skeletal portions of arms and legs, and the genital organs. Cholesterol also is a component of the myelin sheath, which is the protective outer covering of nerves.
Although Smith Lemli Opitz syndrome is a relatively rare disorder, molecular geneticists have identified more than 120 unique mutations in the DHCR7 gene that are causative of this condition. As alluded to above, each one of these mutations affects the 7-dehydrocholesterol reductase protein in its own way. For example, one class of mutations results in absolutely no 7-dehydrocholesterol reductase protein being made. Another class of mutations causes a shortened, or truncated, form of the 7-dehydrocholesterol reductase protein to be made.
Further, a third class of mutations alters only one of the many amino acids that comprise the 7-dehydrocholesterol reductase protein. The number and severity of defects seen in any particular individual who has SLOS is directly attributable to the nature of the specific mutation (or mutations) that is present in that individual's two copies of the DHCR7 gene. Generally, those individuals who generate no 7-dehydrocholesterol reductase protein have more numerous and more severe defects than those who generate a version of the 7-dehydrocholesterol reductase protein which merely has a single amino acid change to the normal version of the protein.