title: NPC1: Complete genomic sequence, mutation analysis, and characterization of haplotypes.
abstract: Niemann-Pick type C disease (NP-C) is a rare, autosomal recessive lipid storage disorder. At least 96% of all NP-C patients link to NPC1 which encodes for a lysosomally-targeted protein. We describe the complete genomic sequence of 57,052 kb corresponding to the transcribed region of human NPC1 including several exonic and intronic single nucleotide polymorphisms (SNPs). Sequencing of all exons, splice sites, and the promoter region of NPC1 in 12 unrelated Caucasian NP-C patients revealed nine novel and four known most likely disease-causing mutations. Ten unique mutations found only once in 24 disease alleles were observed in patients being compound heterozygous for two different mutations. Two of the three missense mutations identified more than once were observed in a total of four patients homozygous for the respective mutation along with homozygosity for the underlying haplotype. The patients were offspring of most likely nonconsanguineous couples. Based upon genotyping exonic SNPs c.2572A>G (I858V; g.45020A>G) and c.2793C>T (N931N; g.45686C>T) and segregation analysis we characterized the haplotype of all 24 NPC1 alleles and of 138 alleles of healthy Caucasian control subjects. All four permutations between the two SNPs were identified in the control alleles: 2572A-2793C (50%), 2572G-2793T (41%), 2572G-2793C (5%), and 2572A-2793T (4%). These data are suggestive for an ancestral intragenic recombination within a genomic fragment of <666 bp. While 17 of 24 NP-C alleles (71%) shared haplotype 2572G-2793T, this haplotype accounted for only 41% in the controls (p=0.007; 2-sided Fisher exact test) suggesting the possibility of an influence of the haplotypic background on expression of missense mutations in NPC1.
authors.affiliation: Universität Rostock, Klinik für Neurologie und Poliklinik, Neurobiologisches Labor, Rostock, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.forename: Rupert
authors.initials: R
authors.lastname: Knoblich
authors.forename: Claudia
authors.initials: C
authors.lastname: Bauer
authors.forename: Ulrich
authors.initials: U
authors.lastname: Finckh
authors.forename: Antje
authors.initials: A
authors.lastname: Hufen
authors.forename: Julia
authors.initials: J
authors.lastname: Kropp
authors.forename: Silja
authors.initials: S
authors.lastname: Braun
authors.forename: Birgit
authors.initials: B
authors.lastname: Kustermann-Kuhn
authors.forename: Dörthe
authors.initials: D
authors.lastname: Schmidt
authors.forename: Klaus
authors.initials: K
authors.lastname: Harzer
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
mesh_terms: D002352:Carrier Proteins / Q000235:genetics*; D016386:Chromosome Walking / Q000379:methods; D004247:DNA / Q000235:genetics; D004252:DNA Mutational Analysis; D017931:DNA Primers / Q000235:genetics; D005260:Female; D006580:Genetic Carrier Screening; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000235:genetics*; D010375:Pedigree; D020161:Physical Chromosome Mapping / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D044465:White People / Q000235:genetics
chemical_list: D002352:Carrier Proteins; D017931:DNA Primers; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D004247:DNA