title: Molecular analysis of 30 Niemann-Pick type C patients from Spain.
abstract: Mutations in the NPC1 or NPC2 gene are responsible for Niemann-Pick type C (NPC) disease (OMIM #257220), an autosomal recessive neurodegenerative lysosomal storage disorder caused by an incorrect regulation of intracellular lipid trafficking. A molecular analysis carried out in 30 unrelated patients identified 43 distinct mutations in the NPC1 gene, 12 of which had not been previously described. The novel NPC1 alleles were four amino acid substitutions (p.F995L, p.F1079S, p.L1106P and p.G1209E), a nonsense mutation (p.E1089X), a 1-bp insertion (p.L1117PfsX4), an in-frame deletion (p.N916del), four intronic changes (c.58-3280C>G, c.882-28A>T, c.2604+5G>A and c.3591+5G>A) that affect the splicing mechanism, and the first deletion including the whole gene described in NPC disease. In all the splice site mutations, the formation of abnormal spliced transcripts was confirmed by cDNA analysis, and mRNA degradation by the nonsense-mediated mRNA decay process was also assessed. As it has been previously reported in this disease, genotype-phenotype correlations are limited due to the large number of private mutations. We describe for the first time one homozygous patient for p.I1061T mutation, who presented the severe infantile clinical onset, and another patient with the variant biochemical phenotype, whose clinical presentation was the neonatal form of the disease.
authors: Institut de Bioquímica Clínica, Servei de Bioquímica i Genètica Molecular, Hospital Clínic, Barcelona, Spain.
authors: J
authors: J
authors: Macías-Vidal
authors: L
authors: L
authors: Rodríguez-Pascau
authors: G
authors: G
authors: Sánchez-Ollé
authors: M
authors: M
authors: Lluch
authors: L
authors: L
authors: Vilageliu
authors: D
authors: D
authors: Grinberg
authors: M J
authors: MJ
authors: Coll
mesh_terms: D000293:Adolescent; D000483:Alleles; D019943:Amino Acid Substitution; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D005260:Female; D017353:Gene Deletion; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000235:genetics* / Q000473:pathology*; D022821:RNA Splice Sites; D017384:Sequence Deletion; D013030:Spain; D055815:Young Adult
chemical_list: D002352:Carrier Proteins; D018389:Codon, Nonsense; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D022821:RNA Splice Sites