Molecular analysis of NPC1 and NPC2 gene in 34 Niemann-Pick C Italian Patients: Identification and structural modeling of novel mutations

Tatiana Fancello, Andrea Dardis, Camillo Rosano, Patrizia Tarugi, Barbara Tappino, Stefania Zampieri, Elisa Pinotti, Fabio Corsolini, Simona Fecarotta, Adele D'Amico, Maja Di Rocco, Graziella Uziel, Sebastiano Calandra, Bruno Bembi, Mirella Filocamo

Research output: Contribution to journalArticlepeer-review


Niemann-Pick C, the autosomal recessive neuro-visceral disease resulting from a failure of cholesterol trafficking within the endosomal-lysosomal pathway, is due to mutations in NPC1 or NPC2 genes. We characterized 34 unrelated patients including 32 patients with mutations in NPC1 gene and two patients in NPC2 gene. Overall, 33 distinct genotypes were encountered. Among the 21 unpublished NPC1 alleles, 15 were due to point mutations resulting in 13 codon replacements (p.C100S, p.P237L, p.R389L, p.L472H, p.Y634C, p.S636F, p.V780G, p.Q921P, p.Y1019C, p.R1077Q, p.L1102F, p.A1187V, and p.L1191F) and in two premature stop codons (p.R934X and p.Q447X); a new mutant carried two in cis mutations, p.[L648H;M1142T] and four other NPC1 alleles were small deletions/insertions leading both to frame shifts and premature protein truncations (p.C31WfsX26, p.F284LfsX26, p.E1188fsX54, and p.T1205NfsX53). Finally, the new intronic c.464-2A>C change at the 3′ acceptor splice site of intron 4 affected NPC1 messenger RNA processing. We also found a new NPC2 mutant caused by a change of the first codon (p.M1L). The novel missense mutations were further investigated by two bioinformatics approaches. Panther proein classification system computationally predicted the detrimental effect of all new missense mutations occurring at evolutionary conserved positions. The other bioinformatics approach was based on prediction of structural alterations induced by missense mutations on the NPC1 atomic models. The in silico analysis predicted protein malfunctioning and/or local folding alteration for most missense mutations. Moreover, the effects of the missense mutations (p.Y634C, p.S636F, p.L648H, and p.V780G) affecting the sterol-sensing domain (SSD) were evaluated by docking simulation between the atomic coordinates of SSD model and cholesterol.

Original languageEnglish
Pages (from-to)229-239
Number of pages11
Issue number3
Publication statusPublished - Jul 2009


  • Cholesterol processing impairment
  • Niemann-Pick type C
  • NPC1 and NPC2 mutational spectrum
  • Panther score
  • Structural modeling

ASJC Scopus subject areas

  • Genetics(clinical)
  • Cellular and Molecular Neuroscience
  • Genetics


Dive into the research topics of 'Molecular analysis of NPC1 and NPC2 gene in 34 Niemann-Pick C Italian Patients: Identification and structural modeling of novel mutations'. Together they form a unique fingerprint.

Cite this