LRP5基因D111Y突变导致常染色体显性遗传性1型骨硬化症一家系报道

目的研究1个骨硬化症家系的临床特点和致病基因。方法对1个来自江苏省家系中的6例患者和6名健康家庭成员进行生化指标、骨代谢指标、骨密度检测,并摄胸腰椎正侧位片、颅骨正侧位片、骨盆平片,同时对致病基因低密度脂蛋白受体相关蛋白5(low-density lipoprotein receptor-related protein 5,LRP5)进行Sanger测序,通过SWISS-MODEL网站预测分析LRP5蛋白构象的变化。结果4例成年患者(1例男性和3例女性)身材高大,均出现下颌骨增大,并且在下颚中央可见腭隆凸。4例患者均未发生过骨折。头颅、下颌骨和骨盆摄片可见颅板增厚,蝶鞍扩大,下颌骨增大和长骨骨皮质增厚。所有患者腰椎、股骨颈以及总髋部的骨密度绝对值相对于同年龄同性别人群均显著增高,不同部位的Z值分别为腰椎2~4(6.31±4.03)SD、股骨颈(6.56±2.36)SD、总髋部(7.19±2.03)SD。基因测序结果表明,6例患者均携带LRP5基因2号外显子p.Asp111Tyr(c.331G>T;D111Y)的杂合突变,而其他家庭成员均为野生型(c.331G>G;D111D)。突变蛋白构象预测结果显示,此突变位于LRP5基因2号外显子的氨基末端,即LRP5蛋白的第一个β螺旋发生区域。结论LRP5基因的D111Y突变导致了以良性骨密度增加为特征的临床表型,不增加骨折风险。此突变可能通过改变LRP5蛋白的空间结构激活下游的Wnt信号通路,从而促进成骨细胞的分化与成熟,导致骨硬化症的发生。

One family with osteosclerosis caused by D111Y mutation in the low-density lipoprotein receptor-related protein 5 gene

Objective To investigate the clinical features and pathogenic genes of a family with osteosclerosis.Methods Six patients and six family members from a family in Jiangsu were tested for biochemical parameters,bone metabolic markers,bone mineral density,thoracolumbar anterior lateral slices,skull positive lateral radiographs,and pelvic plain films.Meanwhile,Sanger sequencing was performed to detect gene mutations of the proband and five other family members with high bone mass.The conformation of the mutational low-density lipoprotein receptor-related protein 5(LRP5)protein was predicted by SWISS-MODEL.Results Four adult patients(one male and three females)were tall,with mandibular enlargement and kyphosis in the center of the lower jaw,and none of the four had fractures.Their X ray examination revealed that the skull and long bone cortex was thickened,while the sella and mandible was enlarged.In addition,the absolute values of bone mineral density at each site of all patients were significantly higher as compared with the standard age-and sex-matched adults or adolescent mean reference values,with Z scores of L2-4,femoral neck and total hip being(6.31±4.03)SD,(6.56±2.36)SD,and(7.19±2.03)SD,respectively.The results of genetic sequencing revealed that all six patients carried a heterozygous mutation(c.331G>T;D111Y)in exon 2 of LRP5 gene,while other family members showed wild type(c.331G>G;D111D).Functional prediction indicated that this mutation was located at the amino acid terminal of exon 2 of LRP5 gene,which encodes the firstβ-helix-generating region of LRP5 protein.Conclusion The D111Y mutation in LRP5 gene leads to a clinical phenotype characterized by benign increased bone mineral density without increasing the risk of fracture.This mutation may further affect the downstream Wnt signaling pathway by altering the spatial structure of LRP5 protein,thereby promoting maturation and differentiation of osteoblasts and resulting in osteosclerosis.