Okawa A, Nakamura I, Goto S, Moriya H, Nakamura Y, Ikegawa S
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Japan.
Nat Genet. 1998 Jul;19(3):271-3. doi: 10.1038/956.
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.
脊柱后纵韧带骨化（OPLL）是一种常见的人类脊髓病形式，由脊髓韧带异位骨化压迫脊髓所致。为阐明OPLL的遗传基础，我们一直在研究ttw（踮足行走；先前称为twy）小鼠，这是一种自然发生的突变体，其脊髓韧带骨化表现与人类OPLL非常相似（参考文献3,4）。通过定位候选基因方法，我们确定ttw表型是由编码核苷酸焦磷酸酶的Npps基因中的无义突变（甘氨酸568突变为终止密码子）引起的。该酶通过产生无机焦磷酸来调节软组织钙化和骨矿化，无机焦磷酸是钙化的主要抑制剂。ttw小鼠加速的骨形成特征可能是由于基因产物预测截短导致NPPS功能障碍，从而导致超过三分之一的天然蛋白质丢失。我们的结果可能会为异位骨化机制和人类OPLL的病因学带来新的见解。
