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

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 (NPCI) 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.

The Nova Scotia (type D) form of Niemann-Pick disease is caused by a G3097-->T transversion in NPC1.

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.

Limiting the Niemann-Pick type C critical region to a 1-cM interval.

OBJECTIVE: To refine the position of and isolate the gene responsible for Niemann-Pick Type II (NP Type II) disease, an autosomal, recessive neurodegenerative disorder usually affecting children. The underlying biochemical defect results in an impairment in transport of intracellular cholesterol. This disease has been classified into two subtypes, NPC and NPD. NPD and the major complementation group of NPC both map to chromosome 18q11-12; therefore, they are likely allelic variants. The NP Type II gene was previously localized between microsatellite markers D18S44 and D18S1108. DESIGN: Linkage analysis. SETTING: Pathology department of a university-associated hospital. PATIENTS: An NPC family, including proband, parents and sister. OUTCOME MEASURES: NP Type II disease phenotype and biochemical phenotype (cholesterol esterification). RESULTS: DNA from the individuals in the NPC family was genotyped at 12 microsatellite loci from the critical region. The deduced haplotypes identify a meiotic recombinant that has allowed the distal limit of the critical region to be moved from D18S1108 to D18S1101. CONCLUSION: The NP Type II gene lies proximal to the microsatellite marker D18S1101, within the 1-cM interval between D18S1101 and D18S1398. This represents approximately 1.1 mb on the physical map.

Linkage of Niemann-Pick disease type D to the same region of human chromosome 18 as Niemann-Pick disease type C.

Niemann-Pick type II disease is a severe disorder characterized by accumulation of tissue cholesterol and sphingomyelin and by progressive degeneration of the nervous system. This disease has two clinically similar subtypes, type C (NPC) and type D (NPD). NPC is clinically variable and has been identified in many ethnic groups. NPD, on the other hand, has been reported only in descendants of an Acadian couple who lived in Nova Scotia in the early 18th century and has a more homogeneous expression resembling that of less severely affected NPC patients. Despite biochemical differences, it has not been established whether NPC and NPD are allelic variants of the same disease. We report here that NPD is tightly linked (recombination fraction .00; maximum LOD score 4.50) to a microsatellite marker, D18S480, from the centromeric region of chromosome 18q. Carstea et al. have reported that the NPC gene maps to this same site; therefore we suggest that NPC and NPD likely result from mutations in the same gene.

Respiratory syncytial virus triggers synthesis of IL-6 in BALB/c mouse alveolar macrophages in the absence of virus replication.

Cytokines produced by alveolar macrophages are likely involved in the regulation of the immune response arising from respiratory syncytial virus (RSV) infection. Both infectious and UV-inactivated RSV were effective in inducing BALB/c mouse alveolar macrophages to synthesize increased levels of IL-6 mRNA and secreted IL-6 protein. No increase in IL-1beta (either mRNA or secreted protein) was observed. The augmented production of IL-6 was activated by purified virus and was reduced by pretreating virus with virus-neutralizing antiserum, demonstrating a requirement for virus in the enhanced IL-6 response. The results suggest that the exposure of BALB/c alveolar macrophages to small quantities of RSV (in the absence of detectable virus replication) is sufficient to trigger IL-6 production. The finding that UV-inactivated virus was effective in triggering IL-6 production by mouse alveolar macrophages is similar to that reported in human alveolar macrophages, providing further validation of the BALB/c mouse as a useful animal model for human RSV infection.