Niemann-Pick type C disease

Abstract

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 T → G 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

Diagnosis of Niemann-Pick disease type C with 7-ketocholesterol screening followed by NPC1/NPC2 gene mutation confirmation in Chinese patients

“…Two small deletions, c.3734_3735delCT and c.2972_2973delAG, had been published previously [27,28]. The c.3734_3735delCT was the only recurring mutant in this group, presenting twice (patients 4 and 5), indicating that this may be a comparatively common mutation in the Chinese population.…”

Assessment of plasma chitotriosidase activity, CCL18/PARC concentration and NP-C suspicion index in the diagnosis of Niemann-Pick disease type C: a prospective observational study

“…Across the two periods in the current study, we identified a total of six novel NPC1 variants and 17 NPC1 mutations that have been described previously [2, 17, 30–36]. No causal NPC2 mutations were detected.…”

“…)Classical650Early infantileNPC3Ap. (Pro1007Ala)[36]p. (Asn222Ser)[34]88266 (Neg)60Variant103AdultNPC4Ap.…”

Niemann-Pick disease type C: mutations of NPC1 gene and the course of disease

“…Interestingly, this mutation was found only in genomic DNA, while in associated cDNA it was not detectable (data not shown). This raises the possibility of degradation of mRNA containing premature stop codon (17). In the analyzed family, direct consanguinity was not detected, but both parents trace their origin from the island of Krk: maternal grandparents have second cousins from the village of Linardići (Krk), while paternal grandfather is from Punat (Krk).…”

“…This patient had juvenile onset of symptoms (hepatosplenomegaly at 4 months), but otherwise showed moderate clinical phenotype in comparison to our siblings. Therefore, we presume that in the case of siblings presented here, Q922X mutation (17), causing the formation of a truncated NPC 1 protein of 921 amino acids, had a more severe impact on the clinical outcome than N1156S mutation. Correlation of nonsense mutations of NPC1 and early neurologic onset and shorter life span was suggested earlier (18).…”