Department of Medical Genetics, University of Antwerp, Belgium.
Hum Mutat. 2010 Jul;31(7):E1526-43. doi: 10.1002/humu.21274.
Sclerosteosis is a rare bone dysplasia characterized by greatly increased bone mass, especially of the long bones and the skull. Patients are tall, show facial asymmetry and often have syndactyly. Clinical complications are due to entrapment of cranial nerves. The disease is thought to be due to loss-of-function mutations in the SOST gene. The SOST gene product, sclerostin, is secreted by osteocytes and transported to the bone surface where it inhibits osteoblastic bone formation by antagonizing Wnt signaling. In a small Turkish family with sclerosteosis, we identified a missense mutation (c.499T>C; p.Cys167Arg) in exon 2 of the SOST gene. This type of mutation has not been previously reported and using different functional approaches, we show that it has a devastating effect on the biological function of sclerostin. The affected cysteine is the last cysteine residue of the cystine-knot motif and loss of this residue leads to retention of the mutant protein in the ER, possibly as a consequence of impaired folding. Together with a significant reduced ability to bind to LRP5 and inhibit Wnt signaling, the p.Cys167Arg mutation leads to a complete loss of function of sclerostin and thus to the characteristic sclerosteosis phenotype.
石骨症是一种罕见的骨发育不良，其特征为骨量显著增加，尤其是长骨和颅骨。患者身材高大，表现出面部不对称，常有关节融合。临床并发症是由于颅神经受压所致。该病被认为是由于 SOST 基因突变导致功能丧失。SOST 基因产物骨硬化蛋白由骨细胞分泌，并被运送到骨表面，通过拮抗 Wnt 信号抑制成骨细胞的骨形成。在一个有石骨症的土耳其小家族中，我们在 SOST 基因的第 2 外显子中发现了一个错义突变（c.499T>C；p.Cys167Arg）。这种类型的突变以前没有报道过，我们使用不同的功能方法表明，它对骨硬化蛋白的生物学功能有毁灭性的影响。受影响的半胱氨酸是胱氨酸结基序的最后一个半胱氨酸残基，该残基的丢失导致突变蛋白在 ER 中滞留，可能是由于折叠受损所致。与结合 LRP5 的能力显著降低和抑制 Wnt 信号的能力降低相结合，p.Cys167Arg 突变导致骨硬化蛋白完全丧失功能，从而导致典型的石骨症表型。
