Characteristics of CERT1
CERT1 (also known as COL3A4BP, MRD34, and STARD11) is located on chromosome 5q13.3 and contains 20 exons. CERT1 produces at least three alternatively spliced variants, which are hereafter referred to as isoforms 1-3. The CERT1 isoform 1 transcript consisting of exons 2-11 and 13-19 is the most abundant type and encodes the 598-amino-acid protein CERT. The isoform 2 transcript consisting of exons 2-19, which encodes a long variant of CERT (the 624-amino-acid protein CERTL) is expressed but at lower levels than isoform 1 in most tissue types. The isoform 3 transcript is the longest CERT1 mRNA isoform that encodes a putative very long variant of CERT (the 752-amino-acid protein CERTVL) although CERTVL has not been biochemically identified. RNA sequencing data from human tissues found in the Genotype-Tissue Expression project (https://gtexportal.org/home/) showed that the expression of exon 1 from CERT1 (that is present in isoform 3) is absent or very rare in all human tissues except for the testis.
Dysregulation of CERT by pathogenic dominant mutations
The lipid ceramide is newly synthed in the endoplasmic reticulum (ER) and is converted to its phosphocholine-conjugated form, sphingomyelin, in the Golgi apparatus. CERT and CERTL mediate the ER-to-Golgi transport of ceramide at ER-Golgi membrane contact zones. Multiple phosphorylations in a serine-repeat motif (SRM), which corresponds to the S132MVSKVSGASGYSATSTSS150 region in the human CERT, result in its functional repression. Various missense mutations in or outside the SRM are associated with dominant inherited intellectual disability/mental development (ID/MD). As far as biochemically analyzed instances, ID/MD-associated variants in CERT1 generally impair the SRM phosphorylation-dependent repression of the CERT functionality.
Suspected pathophysiological mechanism
ID/MD-associated CERT1 mutations display heterozygous dominant characteristics, which can be explained and this dominancy can be accounted for by abnormal activation of CERT variants due to the deficiency in the SRM-phosphorylation-dependent repression. However, it remains unclear how abnormal activation of CERT causes ID/MD. If the enhancement of inter-organelle transport ceramide by the mutations is the main pathogenic cause, controlling the enhanced activity to the normal level using a chemical inhibitor of CERT might be a rational way to improve the pathogenicity.
Appendix
CERT1 is a unique gene (there is no paralog) in the human genome while CERT1 orthologs are widely present in multicellular animals, but absent in plants, single-cell eukaryotes, and bacteria. This phylogenetic distribution pattern of CERT1 orthologs resembles that of the lipid sphingomyelin, implying that CERT and sphingomyelin have somehow co-evolved.
CERT1