desmosterolosis At least seven mutations in the DHCR24 gene have been found to cause desmosterolosis. Desmosterolosis is a condition that is characterized by neurological problems, such as brain abnormalities and developmental delay, and can also include other signs and symptoms. The mutations that cause this condition change single protein building blocks (amino acids) in the 24-dehydrocholesterol reductase enzyme. As a result, enzyme activity is reduced and cholesterol production is decreased. Because the brain relies solely on cellular production for cholesterol, it is most severely affected. Without adequate cholesterol, cell membranes are not formed properly and nerve cells are not protected by myelin, leading to the death of these cells. In addition, a decrease in cholesterol production has more severe effects before birth than during other periods of development because of the rapid increase in cell number that takes place. Disruption of normal cell formation before birth likely accounts for the additional developmental abnormalities of desmosterolosis.

     The DHCR24 gene provides instructions for making an enzyme called 24-dehydrocholesterol reductase. This enzyme is involved in multiple pathways that produce cholesterol. Cholesterol is a waxy, fat-like substance that can be obtained from foods that come from animals (particularly egg yolks, meat, poultry, fish, and dairy products). It can also be produced in various tissues in the body. For example, the brain cannot access the cholesterol that comes from food, so brain cells must produce their own. In one pathway, 24-dehydrocholesterol reductase is involved in the final step of cholesterol production (synthesis), converting the fat desmosterol into cholesterol. In a different pathway, 24-dehydrocholesterol reductase converts the fat lanosterol into another fat called 24,25-dihydrolanosterol. The end product of both of these pathways is cholesterol. Cholesterol is necessary for normal embryonic development and has important functions both before and after birth. Cholesterol is an important component of cell membranes and the fatty protective covering that insulates nerves (myelin). Cholesterol also attaches (binds) to certain proteins to turn on (activate) the hedgehog signaling pathway, which is critical for normal development of many parts of the body before birth. Additionally, cholesterol plays a role in the production of certain hormones and digestive acids.

The following transcription factors affect gene expression:

• p53

Tissue specificity:

Highly expressed in brain and adrenal gland with moderate expression in liver, lung, spleen, prostate and spinal cord. Low expression in heart, uterus and prostate. Undetectable in blood cells. In the brain, strongly expressed in cortical regions, substantia nigra, caudate nucleus, hippocampus, medulla oblongata and pons. In brains affected by Alzheimer disease, expression in the inferior temporal lobe is substantially lower than in the frontal cortex.

Molecular Function:

• Delta24(24-1) Sterol Reductase Activity
• Oxidoreductase Activity, Acting On Ch-Oh Group Of Donors
• Oxidoreductase Activity, Acting On The Ch-Ch Group Of Donors, Nad Or Nadp As Acceptor
• Enzyme Binding
• Peptide Antigen Binding
• Delta24-Sterol Reductase Activity
• Flavin Adenine Dinucleotide Binding

Biological Processes:

• Cholesterol Biosynthetic Process
• Apoptotic Process
• Response To Oxidative Stress
• Cell Cycle Arrest
• Ras Protein Signal Transduction
• Protein Localization
• Negative Regulation Of Cell Proliferation
• Response To Hormone
• Tissue Development
• Male Genitalia Development
• Plasminogen Activation
• Cholesterol Biosynthetic Process Via Desmosterol
• Cholesterol Biosynthetic Process Via Lathosterol
• Amyloid Precursor Protein Catabolic Process
• Negative Regulation Of Apoptotic Process
• Negative Regulation Of Cysteine-Type Endopeptidase Activity Involved In Apoptotic Process
• Skin Development
• Oxidation-Reduction Process
• Membrane Organization
• Regulation Of Neuron Death