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Journal of Lipid Research, Vol. 43, 1908-1919, November 2002
Copyright © 2002 by Lipid Research, Inc.

Niemann-Pick type C disease

Patrizia Tarugi^*, Giorgia Ballarini, Bruno Bembi, Carla Battisti, Silvia Palmeri, Francesca Panzani^*, Enza Di Leo^*, Cristina Martini, Antonio Federico and Sebastiano Calandra^1,*

^* Dipartimento di Scienze Biomediche, Università di Modena e Reggio Emilia, Modena, Italy
Istituto di Scienze Neurologiche, Università di Siena, Siena, Italy
Istituto Pediatrico "Burlo Garofolo,", Trieste, Italy

¹ To whom correspondence should be addressed. e-mail: sebcal{at}unimo.it

We analyzed Niemann-Pick type C disease 1 (NPC1) gene in 12 patients with Niemann-Pick type C disease by sequencing both cDNA obtained from fibroblasts and genomic DNA. All the patients were compound heterozygotes. We found 15 mutations, eight of which previously unreported. The comparison of cDNA and genomic DNA revealed discrepancies in some subjects. In two unrelated patients carrying the same mutations (P474L and nt 2972del2) only one mutant allele (P474L), was expressed in fibroblasts. The mRNA corresponding to the other allele was not detected even in cells incubated with cycloheximide. The promoter variants (-1026T/G and -1186T/C or -238 C/G), found to be in linkage with 2972del2 allele do not explain the lack of expression of this allele, as they were also found in control subjects. In another patient, (N1156S/Q922X) the N1156S allele was expressed in fibroblasts while the expression of the other allele was hardly detectable. In a fourth patient cDNA analysis revealed a point mutation in exon 20 (P1007A) and a 56 nt deletion in exon 22 leading to a frameshift and a premature stop codon. The first mutation was confirmed in genomic DNA; the second turned out to be a TG transversion in exon 22, predicted to cause a missense mutation (V1141G). In fact, this transversion generates a donor splice site in exon 22, which causes an abnormal pre-mRNA splicing leading to a partial deletion of this exon.

In some NPC patients, therefore, the comparison between cDNA and genomic DNA may reveal an unexpected expression of some mutant alleles of NPC1 gene.

Abbreviations: NPC1, Niemann-Pick type C disease 1; NPC2, Niemann-Pick type C disease 2; RT-PCR, reverse transcription and PCR amplification

Supplementary key words monoallelic expression • abnormal mRNA decay • splicing defects • alternative splicing

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