caa a22 4500 397574622 CHVBK 20180308164851.0 cr unu---uuuuu 161202e199612 xx s 000 0 eng 10.1093/hmg/5.12.1977 doi (NATIONALLICENCE)oxford-10.1093/hmg/5.12.1977 Molecular and Biochemical Analysis of Protective Protein/Cathepsin A Mutations: Correlation with Clinical Severity in Galactosialidosis [Elektronische Daten] [Xiao-Yan Zhou, Aarnoud van der Spoel, Robbert Rottier, Greg Hale, Rob Willemsen, Gerard T. Berry, Pietro Strisciuglio, Generoso Andria, Alessandra 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. © 1993 Oxford University Press Zhou Xiao-Yan Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA aut van der Spoel Aarnoud Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA aut Rottier Robbert Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA aut Hale Greg Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA aut Willemsen Rob Department of Cell Biology and Genetics, Erasmus University, Medical Faculty, 3000 DR Rotterdam, The Netherlands aut Berry Gerard T. Department of Pediatrics, Division of Biochemical Development and Molecular Diseases, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA aut Strisciuglio Pietro Department of Pediatrics, University of Reggio Calabria, Catanzaro 88100, Italy aut Andria Generoso Department of Pediatrics, Federico II University, Napoli 80131, Italy aut d'Azzo Alessandra Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA aut Human Molecular Genetics Oxford University Press 5/12(1996-12), 1977-1987 0964-6906 5:12<1977 1996 5 hmg https://doi.org/10.1093/hmg/5.12.1977 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1093/hmg/5.12.1977 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Zhou Xiao-Yan Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA aut NATIONALLICENCE 700 1- van der Spoel Aarnoud Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA aut NATIONALLICENCE 700 1- Rottier Robbert Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA aut NATIONALLICENCE 700 1- Hale Greg Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA aut NATIONALLICENCE 700 1- Willemsen Rob Department of Cell Biology and Genetics, Erasmus University, Medical Faculty, 3000 DR Rotterdam, The Netherlands aut NATIONALLICENCE 700 1- Berry Gerard T. Department of Pediatrics, Division of Biochemical Development and Molecular Diseases, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA aut NATIONALLICENCE 700 1- Strisciuglio Pietro Department of Pediatrics, University of Reggio Calabria, Catanzaro 88100, Italy aut NATIONALLICENCE 700 1- Andria Generoso Department of Pediatrics, Federico II University, Napoli 80131, Italy aut NATIONALLICENCE 700 1- d'Azzo Alessandra Department of Genetics, St Jude Children's Research Hospital, Memphis, TN 38105, USA aut NATIONALLICENCE 773 0- Human Molecular Genetics Oxford University Press 5/12(1996-12), 1977-1987 0964-6906 5:12<1977 1996 5 hmg Metadata rights reserved CC BY-NC-4.0 http://creativecommons.org/licenses/by-nc/4.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-oxford