title: Mutation in Npps in a mouse model of ossification of the posterior longitudinal ligament of the spine.
abstract: Ossification of the posterior longitudinal ligament of the spine (OPLL) is a common form of human myelopathy caused by a compression of the spinal cord by ectopic ossification of spinal ligaments. To elucidate the genetic basis for OPLL, we have been studying the ttw (tiptoe walking; previously designated twy) mouse, a naturally occurring mutant which exhibits ossification of the spinal ligaments very similar to human OPLL (refs 3,4). Using a positional candidate-gene approach, we determined the ttw phenotype is caused by a nonsense mutation (glycine 568 to stop) in the Npps gene which encodes nucleotide pyrophosphatase. This enzyme regulates soft-tissue calcification and bone mineralization by producing inorganic pyrophosphate, a major inhibitor of calcification. The accelerated bone formation characteristic of ttw mice is likely to result from dysfunction of NPPS caused by predicted truncation of the gene product, resulting in the loss of more than one-third of the native protein. Our results may lead to novel insights into the mechanism of ectopic ossification and the aetiology of human OPLL.
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Okawa
authors.forename: I
authors.initials: I
authors.lastname: Nakamura
authors.forename: S
authors.initials: S
authors.lastname: Goto
authors.forename: H
authors.initials: H
authors.lastname: Moriya
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.forename: S
authors.initials: S
authors.lastname: Ikegawa
mesh_terms: D000818:Animals; D001483:Base Sequence; D004252:DNA Mutational Analysis; D018076:DNA, Complementary; D004195:Disease Models, Animal; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D017846:Longitudinal Ligaments; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D017887:Ossification of Posterior Longitudinal Ligament / Q000201:enzymology* / Q000235:genetics*; D011755:Pyrophosphatases / Q000235:genetics*; D013131:Spine / Q000002:abnormalities
chemical_list: D018076:DNA, Complementary; D011755:Pyrophosphatases; C021899:nucleotide pyrophosphatase