1. Niemann-Pick Disease
Maggie W. George
December 5, 2005

2. The Disease
 Condition involving the breakdown and use of fats and
cholesterol in the body
 Harmful amounts of lipids accumulate in the spleen, liver,
lungs, bone marrow, and brain
 Autosomal recessive pattern of inheritance (two copies of the
gene must be present)
 Four variants: A, B, C1, and C2
 Clinical feature include: severe liver disease, breathing
difficulties, developmental delay, seizures, increased muscle
tone, lack of coordination, problems feeding, and inability to
move eyes vertically.
 No treatment

3. Variants
 Types A and B: mutated SMPD1 gene
 SMPD gene carries instructions for cells to produce,
sphingomyelinase, which processes lipids.
 Mutations lead to deficiency of sphingomyelinase and
accumulations of cholesterol and lipids.
 Types C1 and C2: mutated NCP1 or NCP2 gene
 NCP1 gene produces a protein involved in the movement of
cholesterol and lipids within a cell.
 May be a cholesterol pump, which is why its mutation leads
to the buildup of lipids and cholesterol in the cell membrane.
 Plays a critical role in regulation of intracellular cholesterol
trafficking
 NCP2 gene produces protein that binds and transports
cholesterol (not fully understood).

4. NCP1 v. NCP2 Gene
 95% of patients have mutations in the NPC1 gene
 Mapped at chromosome 18q11
 NPC1 encodes a 1278 amino acid glycoprotein with 13
transmembrane domains.
 Remainder of patients have mutations in the NPC2 gene (or
HE1 gene)
 Mapped at chromosome 14q24.3
 Encodes a small soluble lysosomal protein involved in
cholesterol binding.
 Both genes have identical biochemical patterns suggesting that
the two proteins function together in cellular transport of
cholesterol, glycolipids, etc.
 Work together to facilitate the intracellular transport of lipids
from the lysosome to other cellular sites.
 Their precise functions and relationship remain unclear and are
currently the subject of intense investigation.

5. NCP1 Mutations
 Over 130 mutations have been identified in NPC1
 Results in Niemann-Pick Disease Type C1
 Most found within a NPC1 specific cysteine-rich domain, suggesting that the
integrity of this region is crucial for normal functioning of the protein.
 Mutations include: missense mutations, small deletions that generate
premature stop codons, intronic mutations predicted to alter splicing, and
point mutations.
Specific mutation examples:
 exon 20 c.2932 C>T
 c.882-28 A>G (note that patients with this mutation had fibroblasts
containing small amounts of mRNA without exon 7)
 point mutation in exon 20 (causing frameshift and premature stop codon)
 1553G-A transition (causing a splicing error of exon 9)
 2783A-C transversion that results in a gln928-to-pro amino acid
substitution
 3263A-G transition leading to a tyr1088-to-cys amino acid substitution
 530G-A change in exon 5, resulting in a cys177-to-tyr substitution
 4-bp deletion, TTAC

6. NCP2 Mutations
 Results in Niemann-Pick Disease Type C2 and frontal lobe atrophy
 Single amino acid changes prevents both cholesterol binding and the restoration of
normal cholesterol levels in mutant cells.
Specific mutation examples: 16 mutant alleles were identified representing only 5 different
mutations (all had a severe impact on the protein):
1. 2 nonsense mutations, glu20 to ter (E20X): associated with severe rapid disease course
• Results in a frameshift in exon 2, which generates a stop codon 4 codons downstream of
frameshift
• Lung involvement  death from respiratory failure
1. Glu118 to ter substitution (E118X)
• Result of a G-to-T transversion at nucleotide 352 in exon 1 of HE1 gene
1. 1-bp deletion (27delG)
2. Splice mutation (IVS2+5G-A): very difference clinical presentation
• Milder phenotype
• Childhood onset of neurologic symptoms but prolonged survival
1. Missense mutation (S67P)  resulting in reduced amts of abnormal HE1 protein.
*E20X was established as the most common mutant allele (56% frequency)

7. Lack of Knowledge
 Unfortunately, the NCP1 and the NCP2
gene are not fully understood, which means
there is no proposed structure for either.
 There is a structure for the NCP2 bovine
gene, but then again there is little
information about the actual mutations
involved.

8. Human to Bovine Relationship

11. References
 http://en.wikipedia.org/wiki/Niemann-Pick_disease
 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Search
 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed
 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
db=PubMed&cmd=Retrieve&list_uids=12401890
 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
db=PubMed&cmd=Retrieve&list_uids=15774455
 http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?
db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_u
ids=12974729&query_hl=1&itool=pubmed_docsum