Carriers of the Glu167Lys coding variant in the TM6SF2 gene have recently been identified as being more susceptible to
non-alcoholic fatty liver disease (
NAFLD), yet exhibit lower levels of circulating
lipids and hence are protected against
cardiovascular disease. Despite the physiological importance of these observations, the molecular function of TM6SF2 remains unknown, and no sequence similarity with functionally characterized
proteins has been identified. In order to trace its evolutionary history and to identify functional domains, we embarked on a computational
protein sequence analysis of TM6SF2. We identified a new domain, the EXPERA domain, which is conserved among TM6SF, MAC30/TMEM97 and EBP (D8, D7
sterol isomerase)
protein families. EBP mutations are the cause of
chondrodysplasia punctata 2 X-linked dominant (CDPX2), also known as
Conradi-Hünermann-Happle syndrome, a defective
cholesterol biosynthesis disorder. Our analysis of evolutionary conservation among EXPERA domain-containing families and the previously suggested catalytic mechanism for the EBP
enzyme, indicate that TM6SF and MAC30/TMEM97 families are both highly likely to possess, as for the EBP family, catalytic activity as
sterol isomerases. This unexpected prediction of enzymatic functions for TM6SF and MAC30/TMEM97 is important because it now permits detailed experiments to investigate the function of these key
proteins in various human pathologies, from
cardiovascular disease to
cancer.