Sialidosis and galactosialidosis: Chromosomal assignment of two genes associated with neuraminidase-deficiency disorders (sialidase/gene mapping/complementation analysis)

The inherited human disorders sialidosis and galactosialidosis are the result of deficiencies of glycoprotein. specific a-neuramlnidase (acylneuraminyl hydrolase, EC 3.2.1.18; slalidase) activity. Two genes were determined to be necessary for expression of neuraminidase by using human- mouse somatic ceUl hybrids segregating human chromosomes. A panel of mouse RAG-human hybrid cells demonstrated a single-gene requirement for human neuraminidase and allowed assignment of this gene to the (pter-_q23) region of chromo- some 10. A second panel of mouse thymidine kinase (TK)- deficient LM/TKT-human hybrid cells demonstrated that human neuraminidase activity required both chromosomes 10 and 20 to be present. Analysis of human neuraminidase expression in interspecific hybrid ceUls or polykaryocytes formed from fusion of mouse RAG (hypoxanthine/guanine phosphoribosyltransferase deficient) or LM/TK- ceUl lines with human sialidosis or galactosialidosis fibroblasts Indicated that the RAG cell line complemented the galactosialidosis defect, but the LM/TK- cell line did not. This eliminates the requirement for this gene in RAG-human hybrid cells and explains the different chromosome requirements of these two hybrid panels. Fusion of LM/TK- cell hybrids lacking chro- mosome 10 or 20 (phenotype 10+,20- and 10-,20+) and neuraminidase-deficient fibroblasts confrmed by complemen- tation analysis that the sialidosis disorder results from a mutation on chromosome 10, presumably encoding the neuraminidase structural gene. Galactosialidosis is caused by a mutation in a second gene required for neuraminidase expres- sion located on chromosome 20.