The Nova Scotia (Type D) Form of Niemann-Pick Disease Is Caused by a G3097→T Transversion in NPC1

Abstract

Niemann-Pick type D (NPD) disease is a progressive neurodegenerative disorder characterized by the accumulation of tissue cholesterol and sphingomyelin. This disorder is relatively common in southwestern Nova Scotia, because of a founder effect. Our previous studies, using classic linkage analysis of this large extended kindred, defined the critical gene region to a 13-cM chromosome segment between D18S40 and D18S66. A recently isolated gene from this region, NPC1, is mutated in the majority of patients with Niemann-Pick type C disease. We have identified a point mutation within this gene (G3097-->T; Gly992-->Trp) that shows complete linkage disequilibrium with NPD, confirming that NPD is an allelic variant of NPC1.

Clinical-biochemical correlation in molecularly characterized patients with Niemann-Pick type C

“…Our findings confirm previous reports that focused on the differences in esterification and cholesterol homeostasis between cells obtained from patients with the classical NP-C phenotype as compared with cells obtained from the Nova Scotian milder phenotype. 9,10 Indeed, two individuals with "moderate" biochemical phenotype (AM, SG) had the same mutation as that described in the Nova Scotian genetic isolate 17,24 (Table 1).…”

“…A G992W mutation previously detected in the Nova Scotian genetic isolate 17 was found in two independent Muslim Arab families originating from the northern part of Israel (AM and SG). We examined four affected individuals in these families and found the phenotypic severity to be similar to that previously described in the Nova Scotian patients.…”

“…The two known exceptions are a common I1061T mutation found in the Hispanic population in the upper Rio Grande Valley in the southwestern United States, and in the United Kingdom, and France 15 and the mutation G992W in the Acadian population of Nova Scotia. 17 According to accumulated data so far, NPC1 is associated with approximately 80% of known cases; however, both linkage techniques and cellular complementation studies have shown the existence of genetic heterogeneity, providing proof for the presence of an additional disease-causing gene. 18 Recently, HE1 encoding a ubiquitously expressed lysosomal cholesterol binding protein was identified as a second gene for NP-C. 19 NP-C patients from both complementation groups demonstrate similar clinical and biochemical phenotypes, suggesting that NPC1 and HE1 may interact or function sequentially in a common metabolic pathway.…”

Niemann–Pick Type C Mutations Cause Lipid Traffic Jam

“…NPC1 accounts for 95% of the clinical cases. In the general population, multiple distinct NPC1 gene mutations are found (23), whereas affected individuals in the French Acadian population of Nova Scotia have a common mutation (24). The second disease locus, NPC2, accounts for approximately 5% of known cases (25,26).…”

Treatment of Human Fibroblasts Carrying NPC1 Missense Mutations with MG132 Leads to an Improvement of Intracellular Cholesterol Trafficking

“…Only three relative frequent mutations have been found within distinct patient groups: the p.G992W, almost exclusively seen in Acadian patients from Nova Scotia (Greer et al 1998), the p.P1007A found in about 15% of mutated alleles in different European populations (Ribeiro et al 2001;Fancello et al 2009) and the p.I1061T that accounts for 15-20% of mutated alleles in Western Europe and USA (Millat et al 1999;Sun et al 2001;Park et al 2003;Millat et al 2005). However, a study performed in 44 Italian NPC patients showed that the p.I1061T mutation is much less common in Italy, representing only a 4.7% of the NPC1 alleles (Fancello et al 2009).…”