Linkage disequilibrium mapping of the Nova Scotia variant of Niemann-Pick disease

• Published in: Clinical genetics 1999-04, Vol.55 (4), p.248-255
• Main Authors: Greer, WL, Riddell, DC, Murty, S, Gillan, TL, Girouard, GS, Sparrow, SM, Tatlidil, C, Dobson, MJ, Neumann, PE
• Format: Article
• Language: English
• Subjects: Base Sequence; Biological and medical sciences; Carrier Proteins; Chromosomes, Artificial, Yeast; DNA Primers; Errors of metabolism; Expressed Sequence Tags; Female; Founder Effect; Genetic Markers; Humans; Linkage Disequilibrium; linkage disequilibrium mapping; Lipids (lysosomal enzyme disorders, storage diseases); Male; Medical sciences; Membrane Glycoproteins; Metabolic diseases; Microsatellite Repeats; microsatellites; Niemann-Pick Diseases - ethnology; Niemann-Pick Diseases - genetics; Niemann-Pick Type D; Nova Scotia; Pedigree; Proteins - genetics; Sequence Tagged Sites
• ISSN: 0009-9163; 1399-0004
• DOI: 10.1034/j.1399-0004.1999.550406.x

Niemann–Pick type D (NPD) disease is a severe degenerative disorder of the nervous system characterized by the accumulation of tissue cholesterol and sphingomyelin. Because of a founder effect, it is unusually common in southwestern Nova Scotia, Canada. We have confirmed that almost all patients from 20 affected sibships descended on both sides from a small group of Acadians who settled in this region in about the year 1767. Previously using classic linkage analysis of this large kindred, we defined the critical gene region to a 13‐cM chromosome segment between D18S869 and D18S66. Seven ESTs have been positioned within this interval. Carstea et al. (Niemann–Pick C disease gene: homology to mediators of cholesterol homeostasis. Science 1997: 277: 232–235) recently demonstrated that one of these ESTs is the Niemann–Pick type C (NPC1) gene, the gene disrupted in most patients with NPC disease, and we have shown that a G3097→T mutation in the NPC1 gene is also responsible for NPD. Here we report the development of five new polymorphic microsatellite markers and the testing for complete linkage disequilibrium in our single large NPD kindred that allowed us to reduce the NPD critical region to a 1‐cM (1.3–1.6 Mb) interval between D18S1398 and D18S1108. In contrast, Carstea et al., using classic linkage analysis, required more than 18 unrelated NPC families to reduce the NPC1 critical region to a 5‐cM interval. Our work supports the finding that NPD is an allelic variant of NPC1, and illustrates the power of large kindreds, which are common in Atlantic Canada and other relatively isolated areas, for gene mapping and identification.