Mucolipidosis type IV and the mucolipins

MLIV (mucolipidosis type?IV) is a neurodegenerative lysosomal storage disorder caused by mutations in MCOLN1, a gene that encodes TRPML1 (mucolipin-1), a member of the TRPML (transient receptor potential mucolipin) cation channels. Two additional homologues are TRPML2 and TRPML3 comprising the TRPML subgroup in the TRP superfamily. The three proteins play apparently key roles along the endocytosis process, and thus their cellular localization varies among the different group members. Thus TRPML1 is localized exclusively to late endosomes and lysosomes, TRPML2 is primarily located in the recycling clathrin-independent GPI (glycosylphosphatidylinositol)-anchored proteins and early endosomes, and TRPML3 is primarily located in early endosomes. Apparently, all three proteins' main physiological function underlies Ca(2+) channelling, regulating the endocytosis process. Recent findings also indicate that the three TRPML proteins form heteromeric complexes at least in some of their cellular content. The physiological role of these complexes in lysosomal function remains to be elucidated, as well as their effect on the pathophysiology of MLIV. Another open question is whether any one of the TRPMLs bears additional function in channel activity.     

Mucolipidosis I: Increased sialic acid content and deficiency of an α-N-acetylneuraminidase in cultured fibroblasts

Extracts of fibroblasts derived from a patient with mucolipidosis I exhibited a fivefold increase in sialic acid content as compared to those of normal cells. About 80% of this sialic acid was linked to other molecules. Using neuraminlactose as a substrate, mucolipidosis I fibroblasts were found to be severely deficient in an “acid” α-N-acetylneuraminidase. Since other lysosomal hydrolase activities were normal, we hypothesize that the basic metabolic lesion in mucolipidosis I lies in a defective degradation of sialic acid-containing compounds due to the genetic deficiency of a neuraminidase.