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

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

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).

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.

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 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

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 2.Glu118 to ter substitution (E118X) Result of a G-to-T transversion at nucleotide 352 in exon 1 of HE1 gene 3.1-bp deletion (27delG) 4.Splice mutation (IVS2+5G-A): very difference clinical presentation Milder phenotype Childhood onset of neurologic symptoms but prolonged survival 5.Missense mutation (S67P)  resulting in reduced amts of abnormal HE1 protein. *E20X was established as the most common mutant allele (56% frequency)

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.

Human to Bovine Relationship

References   Search&db=books&doptcmdl=GenBookHL&term=%23 10+AND+gnd%5Bbook%5D+AND %5Buid% 5D&rid=gnd.section Search&db=books&doptcmdl=GenBookHL&term=%23 10+AND+gnd%5Bbook%5D+AND %5Buid% 5D&rid=gnd.section.231  bMed&cmd=Retrieve&list_uids= bMed&cmd=Retrieve&list_uids=  bMed&cmd=Retrieve&list_uids= bMed&cmd=Retrieve&list_uids=  bMed&cmd=Retrieve&list_uids= bMed&cmd=Retrieve&list_uids=  bmed&cmd=Retrieve&dopt=AbstractPlus&list_uids= &query_hl=1&itool=pubmed_docsum bmed&cmd=Retrieve&dopt=AbstractPlus&list_uids= &query_hl=1&itool=pubmed_docsum