A MUTATION IN A HIGHLY CONSERVED REGION IN BRUSH-BORDER SUCRASE-ISOMALTASE AND LYSOSOMAL ALPHA-GLUCOSIDASE RESULTS IN GOLGI RETENTION

A point mutation in the cDNA of human intestinal sucrase-isomaltase ha s been recently identified in phenotype II of congenital sucrase-isoma ltase deficiency. The mutation results in a substitution of glutamine by proline at position 1098 (Q1098P) in the sucrase subunit. Expressio n of this mutant sucrase-isomaltase cDNA in COS-1 cells results in an accumulation of sucrase-isomaltase in the ER, intermediate compartment and the cis-Golgi cisternae similar to the accumulation in phenotype II intestinal cells. An interesting feature of the Q1098P substitution is its location in a region of the sucrase subunit that shares striki ng similarities with the isomaltase subunit and other functionally rel ated enzymes, such as human lysosomal acid alpha-glucosidase and Schwa nniomyces occidentalis glucoamylase. We speculated that the Q-->P subs titution in these highly conserved regions may result in a comparable accumulation. Here we examined this hypothesis using lysosomal alpha-g lucosidase as a reporter gene. Mutagenesis of the glutamine residue at position 244 in the homologous region of alpha-glucosidase to proline results in a protein that is neither transported to the lysosomes nor secreted extracellularly but accumulates in the ER, intermediate comp artment and cis-Golgi as a mannose-rich polypeptide similar to mutant sucrase-isomaltase in phenotype II. We propose that the Q1098P and Q24 4P mutations (in sucrase-isomaltase and alpha-glucosidase, respectivel y) generate structural alterations that are recognized by a control me chanism, operating beyond the ER in the intermediate compartment or ci s-Golgi.