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.