Dysregulation of a lipid transfer protein linked to brain disorders
Advanced studies of human genetics are a big wave in the medical sciences. Collaborative teams of clinical geneticists and bioinformaticians are surfing this wave, rapidly discovering genomic variations associated with specific human disorders. This trend is providing scientific bases for personalized medicines but also new, important questions linked to the basic biochemistry field.
Ceramide transport protein, or CERT, moves the waxy lipids known as ceramides in cells for the synthesis of sphingomyelin, a membrane lipid that is ubiquitous in mammalian cells. In 2007, researchers found that CERT is functionally repressed by multiple phosphorylations of a serine-repeat motif, or SRM, in CERT. At the time, scientists regarded this finding as pure biochemistry of a protein.
However, a decade later, large-scale human genetic studies on intellectual disabilities and mental development disorders, or ID/MD, showed that missense mutations in or near the CERT SRM-encoding regions are associated with a type of autosomal dominant hereditary ID/MD. The dominant inheritance was in line with a prediction from the previous biochemical study that loss of hyperphosphorylation of the SRM renders CERT abnormally active.
Our recent collaborative study confirmed this prediction by demonstrating that substitution of a serine residue in the SRM with other residues similar to variants found in ID/MD patients results in dysregulation of CERT in cultured cells. Nonetheless, several ID/MD-associated missense mutations that occurred in the CERT gene CERT1 also are mapped outside the SRM. This riddle was answered by another recent study showing that a non-SRM variant also compromises the SRM hyperphosphorylation, thereby abnormally activating CERT.
Moreover, cell biological analysis showed that abnormally activated CERT mutants exhibit an aberrant punctate distribution in cells, suggesting that the subcellular distribution pattern is applicable as a diagnostic tool to assess whether a CERT1 variant is an abnormally activated type that may cause ID/MD, although the precise identity of the puncta structure remains undetermined.
Enjoy reading ASBMB Today?
Become a member to receive the print edition monthly and the digital edition weekly.Learn more
Get the latest from ASBMB Today
Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.
Scientists agree that eons ago, a bacterium took up residence inside another cell and became its powerhouse, the mitochondrion. But there are competing theories about the birth of other organelles such as the nucleus and endoplasmic reticulum.
After turning up hundreds of genes with hard-to-predict effects, some scientists are now probing the grander developmental processes that shape face geometry.