DHCR7

The DHCR7 gene encodes the enzyme 7-dehydrocholesterol reductase, which is essential for endogenous synthesis of cholesterol. This gene is located on chromosome 11q12-13 and expression is highest in the adrenal gland, testes, liver, and brain. Expression of DHCR7 is increased when sterol concentrations are low, through the action of sterol regulatory binding proteins (SREBP). Activity of the gene may also be affected by tissue specific transcription and alternative splicing.

The most common mutations in DHCR7 result in lower plasma cholesterol levels (hypocholesterolemia). Around 1 in 10 people with the mutation have normal cholesterol levels, however. As such, physicians tend to only consider further tests based on increased levels of the precursors to cholesterol, including 7-dehydrocholesterol (7DHC).

7DHC is extremely prone to lipid peroxidation and is toxic to cell membranes and organelles in the cell. A lack of DHCR7 enzyme can, then, cause both the problem of low cholesterol and high levels of toxic 7DHC.

High levels of the cholesterol precursor, but low or normal levels of cholesterol certainly suggest something amiss with the enzyme involved in this metabolic step. In some cases, however, the DHCR7 gene itself may be functional, but cholesterol synthesis may be compromised by a lack of enzymatic co-factors, such as NADPH and (possibly) cytochrome p450 oxidoreductase.

If a mutation is found in DHCR7 which leads to very low cholesterol levels, a person will usually be diagnosed with Smith-Lemli-Opitz syndrome (SLOS). This is an autosomal recessive disorder, with more than 130 mutations identified as causative.

Common DHCR7 mutations

Most mutations in DHCr7 (around 87.6%) are single nucleotide polymorphisms or missense mutations. ¹  These reduce enzyme function. In rare cases, null mutations occur, resulting in a complete lack of the enzyme or a completely dysfunctional enzyme.

The most frequently reported mutation in DHCR7 is a switch from G to C in IVS8. ²  This mutation is a nonsense mutation where 134 nucleotides are inserted into the transcript of the gene. Those carrying two copies are severely affected, hence why they would be most likely to come to medical and scientific attention.

This mutation was first reported in the British Isles. Around 1.09% of Caucasians of European heritage are thought to carry at least one copy of the allele.

Less common DHCR7 mutations

Other mutations are less common and include a switch from C to T at 278. The effects of this are less severe in most cases. This 278C>T mutation is most common in people of Italian, Cuban, and Mediterranean descent.

Another nonsense mutation (452C>A) is the third most common affecting DHCR7. This mutation results in no DHCR7 enzyme being synthesized. This is most common in Northern Europe.