Περίληψη:
Morquio A syndrome (MPS IVA) is a systemic lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), encoded by the GALNS gene. We studied 37 MPS IV A patients and defined genotype-phenotype correlations based on clinical data, biochemical assays, molecular analyses, and in silico structural analyses of associated mutations. We found that standard sequencing procedures, albeit identifying 14 novel small GALNS genetic lesions, failed to characterize the second disease-causing mutation in the 16% of the patients' cohort. To address this drawback and uncover potential gross GALNS rearrangements, we developed molecular procedures (CNV [copy-number variation] assays, QF-PCRs [quantitative fluorescent-PCRs]), endorsed by CGH-arrays. Using this approach, we characterized two new large deletions and their corresponding breakpoints. Both deletions were heterozygous and included the first exon of the PIEZO1 gene, which is associated with dehydrated hereditary stomatocitosis, an autosomal-dominant syndrome. In addition, we characterized the new GALNS intronic lesion c.245-11C>G causing m-RNA defects, although identified outside the GT/AG splice pair. We estimated the occurrence of the disease in the Italian population to be approximately 1:300,000 live births and defined a molecular testing algorithm designed to help diagnosing MPS IVA and foreseeing disease progression. © 2014 WILEY PERIODICALS, INC.
Συγγραφείς:
Caciotti, A.
Tonin, R.
Rigoldi, M.
Ferri, L.
Catarzi, S.
Cavicchi, C.
Procopio, E.
Donati, M.A.
Ficcadenti, A.
Fiumara, A.
Barone, R.
Garavelli, L.
Rocco, M.D.
Filocamo, M.
Antuzzi, D.
Scarpa, M.
Mooney, S.D.
Li, B.
Skouma, A.
Bianca, S.
Concolino, D.
Casalone, R.
Monti, E.
Pantaleo, M.
Giglio, S.
Guerrini, R.
Parini, R.
Morrone, A.
Λέξεις-κλειδιά:
Article; biochemical composition; child; clinical article; computer model; copy number variation; exon; female; gene; gene deletion; genetic association; genetic disorder; genotype phenotype correlation; heterozygosity loss; human; human cell; intron; Italian (citizen); live birth; missense mutation; molecular diagnosis; Morquio syndrome; n acetylgalactosamine 6 sulfatase gene; polymerase chain reaction; preschool child; priority journal; sequence analysis; adolescent; adult; cell line; chemistry; cytology; fibroblast; genetics; lymphocyte; male; Mucopolysaccharidosis IV; mutation; phenotype; prognosis; skin; young adult, Iva, GALNS protein, human; isoprotein; messenger RNA; n acetylgalactosamine 4 sulfatase, Adolescent; Adult; Cell Line; Chondroitinsulfatases; Female; Fibroblasts; Humans; Lymphocytes; Male; Mucopolysaccharidosis IV; Mutation; Phenotype; Prognosis; Protein Isoforms; RNA, Messenger; Skin; Young Adult
