Background
Mucolipidosis type IV (MLIV; MIM 252650) is an autosomal recessive lysosomal storage disorder that is characterized by corneal clouding, delayed psychomotor development, and mental retardation that usually presents during the first year of life [1]. Another interesting clinical characteristic is that patients are constitutively achlorhydric with associated hypergastremia [2]. Patients with MLIV do not show mucopolysaccharide excretion, skeletal changes, or organomegaly like the other mucolipidoses. Abnormal lysosomal storage bodies and large vacuoles have been found in skin and conjuctival biopsies using electron-microscopy and, prior to gene identification, served as the only means of diagnosis [3-5]. A recent report estimates that the carrier frequency of MLIV in the Ashkenazi Jewish population is 1 in 100, and mutations have been reported in Jewish and non-Jewish families [6-9].
The human gene MCOLN1 (GenBank #AF287270) maps to chromosome 19p13.2-13.3 and encodes a novel protein that is a member of the transient receptor potential (TRP) cation channel gene superfamily [7-10]. Protein trafficking studies suggest that MLIV is the result of a defect in the late endocytic pathway, contrary to the other mucolipidoses which are typically caused by defective lysosomal hydrolases [11,12]. Recent work in Caenorhabditis elegans supports this hypothesis. Loss of function mutants of the MCOLN1 C. elegans homologue, cup-5, result in an increased rate of endocytosis, accumulation of large vacuoles, and a decreased rate of endocytosed protein breakdown; while over-expression of this gene reverses the phenotype [13]. Cloning and characterization of the mouse homologue of MCOLN1 is crucial for the development of mouse models of MLIV to further study this disorder.