PMID- 10521290
OWN - NLM
STAT- MEDLINE
DCOM- 19991210
LR  - 20211203
IS  - 0002-9297 (Print)
IS  - 0002-9297 (Linking)
VI  - 65
IP  - 5
DP  - 1999 Nov
TI  - Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain.
PG  - 1252-60
AB  - Niemann-Pick type II disease is an autosomal recessive disorder characterized by 
      a defect in intracellular trafficking of sterols. We have determined the
      intron/exon boundaries of eight exons from the conserved 3' portion of NPC1, the 
      gene associated with most cases of the disease. SSCP analyses were designed for
      these exons and were used to identify the majority of mutations in 13 apparently 
      unrelated families. Thirteen mutations were found, accounting for 19 of the 26
      alleles. These mutations included eight different missense mutations (including
      one reported by Greer et al. [1998]), one 4-bp and two 2-bp deletions that
      generate premature stop codons, and two intronic mutations that are predicted to 
      alter splicing. Two of the missense mutations were present in predicted
      transmembrane (TM) domains. Clustering of these and other reported NPC1 mutations
      in the carboxy-terminal third of the protein indicates that screening of these
      exons, by means of the SSCP analyses reported here, will detect most mutations.
      The carboxy-terminal half of the Npc1 protein shares amino acid similarity with
      the TM domains of the morphogen receptor Patched, with the largest stretch of
      unrelated sequence lying between two putative TM spans. Alignment of this portion
      of the human Npc1 protein sequence with Npc1-related sequences from mouse, yeast,
      nematode, and a plant, Arabidopsis, revealed conserved cysteine residues that may
      coordinate the structure of this domain. That 7 of a total of 13 NPC1 missense
      mutations are concentrated in this single Npc1-specific domain suggests that
      integrity of this region is particularly critical for normal functioning of the
      protein.
FAU - Greer, W L
AU  - Greer WL
AD  - Department of Pathology, Division of Molecular Pathology and Molecular Genetics, 
      Dalhousie University, Halifax, Nova Scotia, Canada. plmwlg@qe2-hsc.ns.ca
FAU - Dobson, M J
AU  - Dobson MJ
FAU - Girouard, G S
AU  - Girouard GS
FAU - Byers, D M
AU  - Byers DM
FAU - Riddell, D C
AU  - Riddell DC
FAU - Neumann, P E
AU  - Neumann PE
LA  - eng
SI  - GENBANK/AF125033
SI  - GENBANK/AF125034
SI  - GENBANK/AF125035
SI  - GENBANK/AF125036
SI  - GENBANK/AF125037
SI  - GENBANK/AF125038
SI  - GENBANK/AF125039
SI  - GENBANK/AF125040
SI  - GENBANK/AH009307
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Hum Genet
JT  - American journal of human genetics
JID - 0370475
RN  - 0 (Carrier Proteins)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Membrane Proteins)
RN  - 0 (NPC1 protein, human)
RN  - 0 (Niemann-Pick C1 Protein)
RN  - 0 (Proteins)
RN  - K848JZ4886 (Cysteine)
SB  - IM
MH  - Amino Acid Sequence
MH  - Canada
MH  - *Carrier Proteins
MH  - Cloning, Molecular
MH  - Conserved Sequence/*genetics
MH  - Cysteine/*genetics
MH  - DNA Mutational Analysis
MH  - Exons
MH  - Humans
MH  - Intracellular Signaling Peptides and Proteins
MH  - Introns
MH  - *Membrane Glycoproteins
MH  - Membrane Proteins/chemistry/genetics
MH  - Molecular Sequence Data
MH  - Niemann-Pick C1 Protein
MH  - Niemann-Pick Diseases/*genetics
MH  - Polymorphism, Single-Stranded Conformational
MH  - Proteins/chemistry/*genetics
MH  - Sequence Alignment
PMC - PMC1288277
EDAT- 1999/10/16 09:00
MHDA- 2000/03/21 09:00
CRDT- 1999/10/16 09:00
PHST- 1999/10/16 09:00 [pubmed]
PHST- 2000/03/21 09:00 [medline]
PHST- 1999/10/16 09:00 [entrez]
AID - S0002-9297(07)62131-4 [pii]
AID - 10.1086/302620 [doi]
PST - ppublish
SO  - Am J Hum Genet. 1999 Nov;65(5):1252-60. doi: 10.1086/302620.