Cloning of the gene encoding a novel integral membrane protein, mucolipidin - and identification of the two major founder mutations causing mucolipidosis type IV

Mucolipidosis type IV (MLIV) is an autosomal recessive lysosomal storage di sorder characterized by severe psychomotor retardation and ophthalmologic a bnormalities, including corneal opacity, retinal degeneration, and strabism us. Unlike the situation in other lysosomal disorders, the accumulation of heterogeneous storage material observed in MLIV does not result from a bloc k in the catabolic pathways but is due to an ill-defined transport defect i n the late steps of endocytosis. With the aim of cloning the MLIV gene, we searched in the 19p13.2-13.3 region, where the locus previously had been as signed by linkage mapping. In this region, we have identified a novel gene that is mutated in all patients with MLIV who were enrolled in our study. O ne patient was homozygous for the splice-acceptor mutation, and another was homozygous for a deletion removing the first six exons of the gene. In add ition, four compound heterozygotes for these two mutations were identified. Haplotype analysis indicates that we have identified the two major founder mutations, which account for >95% of MLIV chromosomes in Ashkenazi Jewish patients. The gene, ML4, encodes a protein named "mucolipidin," which local izes on the plasma membrane and, in the carboxy-terminal region, shows homo logies to polycystin-2, the product of the polycystic kidney disease 2 gene (PKD2) and to the family of transient receptor potential Ca2+ channels. Mu colipidin is likely to play an important role in endocytosis.