MUTATION IN NPPS IN A MOUSE MODEL OF OSSIFICATION OF THE POSTERIOR LONGITUDINAL LIGAMENT OF THE SPINE

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(1,2). To eluci date the genetic basis for OPLL, we have been studying the ttw (tiptoe walking; previously designated twy) mouse, a naturally occurring muta nt 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 (glycin e 568 to stop) in the Npps gene which encodes nucleotide pyrophosphata se. This enzyme regulates soft-tissue calcification and bone mineraliz ation by producing inorganic pyrophosphate, a major inhibitor of calci fication(5-8). The accelerated bone formation characteristic of ttw mi ce is likely to result from dysfunction of NPPS caused by predicted tr uncation of the gene product, resulting in the loss of more than one-t hird of the native protein. Our results may lead to novel insights int o the mechanism of ectopic ossification and the aetiology of human OPL L.