Molecular and biochemical analysis of protective proten/cathepsin A mutations: Correlation with clinical severity in galactosialidosis

Xiao Yan Zhou, Aarnoud Van Der Spoel, Robbert Rottier, Greg Hale, Rob Willemsen, Gerard T. Berry, Pietro Strisciuglio, Generoso Andria, Alessandra D'Azzo

Producción científica: Contribución a una revistaArtículorevisión exhaustiva

64 Citas (Scopus)

Resumen

Mutations in the gene encoding lysosomal protective protein/cathepsin A (PRCA) 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 (El), 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.

Idioma originalEnglish
Páginas (desde-hasta)1977-1987
Número de páginas11
PublicaciónHuman Molecular Genetics
Volumen5
N.º12
EstadoPublished - dic. 1996
Publicado de forma externa

ASJC Scopus Subject Areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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