Pangrazio Alessandra, Poliani Pietro Luigi, Megarbane André, Lefranc Gérard, Lanino Edoardo, Di Rocco Maja, Rucci Francesca, Lucchini Franco, Ravanini Maria, Facchetti Fabio, Abinun Mario, Vezzoni Paolo, Villa Anna, Frattini Annalisa
Institute for Biomedical Technologies, CNR, Milan, Italy.
J Bone Miner Res. 2006 Jul;21(7):1098-105. doi: 10.1359/jbmr.060403.
We report three novel osteopetrosis patients with OSTM1 mutations and review two that have been previously described. Our analysis suggests that OSTM1 defines a new subset of patients with severe central nervous system involvement. This defect is also present in the gl mouse, which could represent a good model to study the role of the gene in the pathogenesis of this disease.
Autosomal recessive osteopetrosis (ARO) is a severe hereditary bone disease whose cellular basis is in the osteoclast, but with heterogeneous molecular defects. In addition to the TCIRG1 and the ClCN7 genes, whose mutations account for approximately 55% and 10% of cases, respectively, the OSTM1 gene has been described thus far in only two ARO patients. materials and methods: We report here three novel ARO patients presenting with severe primary central nervous system involvement in addition to the classical stigmata of severe bone sclerosis, growth failure, anemia, thrombocytopenia, and visual impairment with optic atrophy. In addition we analyzed the brain morphology and histology of the grey lethal mutant mouse.
The analysis of the OSTM1 gene in two patients, both from Kuwait, showed homozygous two nucleotide deletion in exon 2, leading to a frameshift and premature termination. The third (Lebanese) patient showed a single point mutation in exon 1, leading to a nonsense mutation. The clinical neurological evaluation of the two Kuwaiti patients by CT and MRI scans showed a defect in the white matter, with a specific diagnosis of severe cerebral atrophy. The gl brain showed a diffuse translucent appearance with loss of the normal demarcation between the white and the grey matter, features consistent with myelin loss or hypomyelination. Histological and myelin staining analysis evidenced an atrophy of the corpus callosum with loss of myelin fibers, and in cortical areas, loss of the normal lamination consistent with multiple foci of cortical dysplasia.
These findings suggest that OSTM1-dependent ARO defines a new subset of patients with severe central nervous system involvement leading to a very poor prognosis. The fact that central nervous system involvement is also present in the gl mouse mutant suggests that this mouse is a good model to test possible therapies.
我们报告了三名患有 OSTM1 突变的新型骨硬化症患者，并回顾了之前描述过的两名患者。我们的分析表明，OSTM1 定义了一个有严重中枢神经系统受累的新患者亚群。这种缺陷在灰色致死小鼠（gl 小鼠）中也存在，它可能是研究该基因在这种疾病发病机制中作用的良好模型。
常染色体隐性遗传性骨硬化症（ARO）是一种严重的遗传性骨病，其细胞基础在于破骨细胞，但存在分子缺陷的异质性。除了 TCIRG1 和 ClCN7 基因，其突变分别约占病例的 55%和 10%外，迄今为止仅在两名 ARO 患者中描述过 OSTM1 基因。材料与方法：我们在此报告三名新型 ARO 患者，除了严重骨硬化、生长发育迟缓、贫血、血小板减少以及伴有视神经萎缩的视力损害等典型体征外，还伴有严重的原发性中枢神经系统受累。此外，我们分析了灰色致死突变小鼠的脑形态学和组织学。
对两名均来自科威特的患者进行 OSTM1 基因分析，发现外显子 2 存在纯合的两个核苷酸缺失，导致移码和过早终止。第三名（黎巴嫩）患者在外显子 1 显示单点突变，导致无义突变。通过 CT 和 MRI 扫描对两名科威特患者进行的临床神经学评估显示白质存在缺陷，明确诊断为严重脑萎缩。gl 小鼠的脑呈现弥漫性半透明外观，白质和灰质之间正常界限消失，这些特征与髓磷脂丢失或髓鞘形成不足一致。组织学和髓磷脂染色分析证明胼胝体萎缩，髓磷脂纤维丢失，在皮质区域，正常分层消失，与多个皮质发育异常灶一致。
这些发现表明，依赖 OSTM1 的 ARO 定义了一个有严重中枢神经系统受累且预后极差的新患者亚群。中枢神经系统受累也存在于 gl 小鼠突变体中的这一事实表明，该小鼠是测试可能疗法的良好模型。
