DHCR7 The gene encoding DHCR7 (labeled as DHCR7) was cloned in 1998, and has been mapped to chromosome 11q12-13. It is 14100 base pairs of DNA in length, and contains nine exons, the corresponding mRNA is 2786 base pairs in length (the remaining DNA sequence is intronic). The structure of the DHCR7 rat gene is very similar to the structure of the human gene. The highest levels of DHCR7 expression have been detected in the adrenal gland, the testis, the liver and in brain tissue. Its expression is induced by decreased sterol concentrations via sterol regulatory binding proteins (SREBP). There is also evidence that its activity may be regulated by tissue specific transcription, and alternative splicing. As outlined above, the enzyme DHCR7 catalyzes the reduction of 7DHC to cholesterol, as well as the reduction of 7-dehydrodesmosterol to desmosterol. It requires NADPH as a cofactor for this reduction, and may involve the activity of cytochrome-P450 oxidoreductase. It is also thought to contain iron. DHCR7 is an integral membrane protein of the endoplasmic reticulum, and computer models have predicted up to nine transmembrane domains. DHCR7 is most efficient at reducing 7DHC, but it is known to reduce the carbon 7 double bond of other sterols, indicating a range of substrate specificity. The human version of this enzyme is predicted to have a molecular weight of 54,489 kDa, and an isoelectric point of 9.05. The amino acid sequence that encodes DHCR7 is predicted to contain 475 amino acids, as well as several protein motifs. It contains multiple sterol reductase motifs, as would be expected given its function. It contains a potential sterol-sensing domain (SSD), whose function is unknown but thought to be necessary for binding sterol substrates. It also includes multiple sites of phosphorylation, including potential protein kinase C and tyrosine kinase sites (regulatory enzymes responsible for phosphorylation). The exact function of phosphorylating DHCR7 is yet unknown, but it is thought to be involved in the regulation of its activity. Mutations and incidence Missense mutations account for 87.6% of the SLOS spectrum SLOS is an autosomal recessive disorder. More than 130 different types of mutations have been identified. Missense mutations (single nucleotide change resulting in a code for a different amino acid) are the most common, accounting for 87.6% of the SLOS spectrum. These typically reduce the function of the enzyme but may not inhibit it completely. Much depends on the nature of the mutation (i.e. which amino acid is replaced and where). Null mutations are much less common, these mutations produce either a completely dysfunctional enzyme, or no enzyme at all. Thus, missense mutations may be more common overall because they are less lethal than nonsense mutations; nonsense mutations may simply result in spontaneous abortion. The IVS8-1G>C is the most frequently reported mutation in DHCR7. This disrupts the joining of exons eight and nine, and results in the insertion of 134 nucleotides into the DHCR7 transcript. This is a nonsense mutation, thus patients that are homozygous for this allele are severely affected. It is thought that this mutation first occurred in the British Isles, and it has a carrier (those that are heterozygous for the allele but not affected) frequency of 1.09% for Caucasians of European heritage. The frequency of mutations differs for various ethnicities, depending on the origin of the mutation. In all Caucasian populations, this particular mutation has an estimated carrier frequency of 3%. The next most common mutation is 278C>T, and results in a threonine at the amino acid position 93. It is a missense mutation and tends to be associated with less severe symptoms. This mutation is the most common one seen in patients of Italian, Cuban, and Mediterranean descent. The third most common mutation is 452G>A. This nonsense mutation causes protein termination, such that the enzyme DHCR7 would not be formed. It is thought to have arisen in Southern Poland and is most common in Northern Europe. Other mutations are less common, although appear to target certain protein domains more so than others. For example, the sterol reductase motifs are common sites of mutation. Overall, there is an estimated carrier frequency (for any DHCR7 mutation causing SLOS) of 3-4% in Caucasian populations (it is less frequent among Asian and African populations). This number indicates a hypothetical birth incidence between 1/2500 and 1/4500. However, the measured incidence is between 1/10,000 to 1/60,000 (it differs depending on heritage and descent). This is much lower than expected. This indicates that many cases of SLOS are undetected, and is likely due to either spontaneous abortion caused by severe mutations (miscarriage), or mild cases that are undiagnosed. Females lack the characteristic genital malformations that affected males have, and thus are less likely to be correctly diagnosed.
Smith–Lemli–Opitz syndrome
DiGeorge syndrome
Li–Fraumeni syndrome
Smith–Magenis syndrome
Wilson–Turner syndrome
Simpson–Golabi–Behmel syndrome
Landau–Kleffner syndrome
Kapur–Toriello syndrome