Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome
Disruption of the Flnb gene in mice phenocopies the human disease spondylocarpotarsal synostosis syndrome
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DOI：
10.1093/hmg/ddm188
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发表时间：
2008-03-01
影响因子：
3.5
通讯作者：
Krakow, Deborah
中科院分区：
文献类型：
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作者：
Farrington-Rock, Claire;Kirilova, Veneta;Krakow, Deborah
脊柱腕跗骨融合综合征（SCT）是一种常染色体隐性遗传疾病，其特征是身材矮小、椎骨与腕骨和跗骨融合。 SCT 是 FLNB 中无义突变的纯合性或复合杂合性的结果。 FLNB 编码细丝蛋白 B，这是一种多功能细胞质蛋白，在骨骼发育中发挥着关键作用。从 FLNB 中存在无义突变的 SCT 患者细胞中提取的蛋白质提取物不含细丝蛋白 B，这表明 SCT 是由于细丝蛋白 B 缺失所致。为了了解细丝蛋白 B 在骨骼发育中的作用，建立了 Flnb(-/-) 小鼠模型。 Flnb(-/-) 小鼠在表型上与 SCT 个体相似，因为它们表现出身材矮小和类似的骨骼异常。新生 Flnb(-/-) 小鼠的颈椎和胸椎椎骨神经弓之间存在融合。出生后第 60 天，椎骨融合更加广泛，涉及椎体和神经弓。此外，胸骨和腕骨也出现融合。对 Flnb(-/-) 小鼠表型的分析表明，Filamin B 的缺失会导致进行性椎体融合，这与之前的假设相反，即 SCT 是由于正常脊柱分割失败所致。这些发现表明，在没有细丝蛋白 B 的情况下，脊柱分割可以正常发生，但该蛋白质是维持椎间关节、腕关节和胸骨关节所必需的，并且关节融合过程在产前就开始了。
Spondylocarpotarsal synostosis syndrome (SCT) is an autosomal recessive disease that is characterized by short stature, and fusions of the vertebrae and carpal and tarsal bones. SCT results from homozygosity or compound heterozygosity for nonsense mutations in FLNB. FLNB encodes filamin B, a multifunctional cytoplasmic protein that plays a critical role in skeletal development. Protein extracts derived from cells of SCT patients with nonsense mutations in FLNB did not contain filamin B, demonstrating that SCT results from absence of filamin B. To understand the role of filamin B in skeletal development, an Flnb(-/-) mouse model was generated. The Flnb(-/-) mice were phenotypically similar to individuals with SCT as they exhibited short stature and similar skeletal abnormalities. Newborn Flnb(-/-) mice had fusions between the neural arches of the vertebrae in the cervical and thoracic spine. At postnatal day 60, the vertebral fusions were more widespread and involved the vertebral bodies as well as the neural arches. In addition, fusions were seen in sternum and carpal bones. Analysis of the Flnb(-/-) mice phenotype showed that an absence of filamin B causes progressive vertebral fusions, which is contrary to the previous hypothesis that SCT results from failure of normal spinal segmentation. These findings suggest that spinal segmentation can occur normally in the absence of filamin B, but the protein is required for maintenance of intervertebral, carpal and sternal joints, and the joint fusion process commences antenatally.