Human Molecular Genetics, Vol 5, 1977-1987, Copyright © 1996 by Oxford University Press
XY Zhou, A van der Spoel, R Rottier, G Hale, R Willemsen, GT Berry, P Strisciuglio, A Morrone, E Zammarchi, G Andria and A d'Azzo
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 present
with either an early infantile (EI), a late infantile (LI), or a
juvenile/adult (J/A) form of the disease. To study genotype-phenotype
correlation in this disorder, we have analyzed the mutations in the PPCA
gene 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, lysosomal
localization and maturation of the mutant precursors. Two amino acid
substitutions (Phe412Val and Tyr221Asn) are shared by five LI patients.
These mutations appear to be pathognomonic for this phenotype, and
determine the clinical outcome depending on whether they are present
together or in combination with other mutations. The latter include a
single base deletion and a novel amino acid change (Met378Thr), which
generates an additional glycosylation site. Within the LI group, patients
carrying the Phe412Val mutation are clinically more severe than those with
the Tyr221Asn substitution. This is in agreement with the biochemical
behavior of the Asn221-mutant protein, that is, like the Phe412Val protein,
phosphorylated, routed to lysosomes and proteolytically processed, but its
intralysosomal stability is intermediate between that of wild-type PPCA and
Val412- PPCA. Overall, these results may explain the clinical heterogeneity
observed in GS patients and may help to correlate mutant allelic
combinations with specific clinical phenotypes.
ARTICLES
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]
Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
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