Correction of human mucolipidosis II enzyme abnormalities in somatic cell hybrids

Abstract

THE mouse genome has been used to correct the abnormal enzyme phenotype of a human neurodegenerative disorder and to provide information on the nature of the molecular defect. This has been demonstrated in man–mouse somatic cell hybrids using human cells derived from an individual with mucolipidosis II. Mucolipidosis II (ML II) or I-cell disease is a rare fatal childhood storage disease which is associated with deficiencies and electrophoretic abnormalities of several lysosomal hydrolases^1–4. Somatic cell hybridisation provides a methodology for examining the expression of mutant genes and for identifying and mapping genes associated with human enzyme abnormalities. We have examined the isozyme patterns of six enzymes altered in this disorder in man–mouse hybrids formed with fibroblasts from an ML II patient. These altered enzymes showed corrected patterns of expression in cell hybrids. Since several human enzymes are corrected, a defect in the post-translational processing of lysosomal enzymes is suggested. Previous studies fusing human lysosomal storage disease cells with rodent cell lines have failed to demonstrate correction of the enzyme deficiencies by the rodent genome^5–8. We present here the first example of the correction of an abnormal enzyme phenotype associated with a human lysosomal storage disease by fusing human and mouse genomes.