Molecular and biochemical analysis of protective protein/cathepsin A mutations: correlation with clinical severity in galactosialidosis [published erratum appears in Hum Mol Genet 1997 Jan;6(1):146]

Mutations in the gene encoding lysosomal protective protein/cathepsin A(PPCA) are the cause of the lysosomal disorder galactosialidosis (GS).Depending on age of onset and severity of the symptoms, patients presentwith either an early infantile (EI), a late infantile (LI), or ajuvenile/adult (J/A) form of the disease. To study genotype-phenotypecorrelation in this disorder, we have analyzed the mutations in the PPCAgene of eight clinically different patients. In two EI and one J/A patient,we have identified four novel point mutations (Val104Met, Leu208Pro,Gly411Ser and Ser23Tyr), that prevent phosphorylation and, hence, lysosomallocalization and maturation of the mutant precursors. Two amino acidsubstitutions (Phe412Val and Tyr221Asn) are shared by five LI patients.These mutations appear to be pathognomonic for this phenotype, anddetermine the clinical outcome depending on whether they are presenttogether or in combination with other mutations. The latter include asingle base deletion and a novel amino acid change (Met378Thr), whichgenerates an additional glycosylation site. Within the LI group, patientscarrying the Phe412Val mutation are clinically more severe than those withthe Tyr221Asn substitution. This is in agreement with the biochemicalbehavior of the Asn221-mutant protein, that is, like the Phe412Val protein,phosphorylated, routed to lysosomes and proteolytically processed, but itsintralysosomal stability is intermediate between that of wild-type PPCA andVal412- PPCA. Overall, these results may explain the clinical heterogeneityobserved in GS patients and may help to correlate mutant alleliccombinations with specific clinical phenotypes.