CLCN7基因突变致常染色体显性遗传性骨硬化症:1例家系研究

Mutation in CLCN7 cause rare autosomal dominant osteopetrosis: a family study

目的分析1例骨硬化症患者的临床特点,并对患者及其家系进行致病基因突变研究。方法纳入1例青年起病,以骨痛、脊柱活动受限为主要表现的女性,评估骨转换生化指标、骨密度、骨骼X线影像特点;采用靶向测序及Sanger直接测序法检测骨硬化症候选基因突变。结果先证者X线片示椎体呈"夹心饼"样改变,髂骨见"骨中骨"现象;腰椎及股骨近端骨密度(bone mineral density,BMD)异常升高,Z值最高达13.8。基因检测示患者及其母亲存在氯离子第7通道蛋白(chloride channel 7,CLCN7)编码基因第16外显子c.1442C>T杂合错义突变(p.Pro481Leu)。患者母亲没有骨硬化症的表现,骨密度符合骨量减少,表明该病具有明显的外显不全现象。患者父亲、弟弟、儿子未发现此突变。c.1442C>T错义突变为CLCN7基因的新突变,本例为首次报道。结论骨硬化症是以骨密度异常增高为特点的罕见遗传性骨病,CLCN7基因c.1442C>T(p.Pro481Leu)错义突变可导致常染色体显性遗传骨硬化症Ⅱ型(autosomal dominant osteopetrosis-Ⅱ,ADO-Ⅱ),本研究丰富了该病的致病基因突变谱。

Objective To investigate /he phenotype of a patient with osteopetrosis and detect the genetic mutation in the patient and her kindred. Methods A woman suffered from bone pain and limitation of spinal mobility from young adulthood. Bone turnover biomarkers, bone mineral density （BMD） , and skeletal X-ray features of the patient were evaluated. Mutations of candidate genes of osteopetrosis were identified by next generation targeted sequencing and were confirmed by Sanger sequencing. Results The proband presented with ＂ sandwich vertebrae＂ sign and typically ＂bone-within-bone＂ in X-ray films, and her BMD was significantly increased at lumbar spine and proximal lemur with the highest Z score to 13.8. A novel heterozygous missense mutation c. 1442C〉T （p. Pro481Leu） in exon 16 of CLCN7 was identified in the proband and her mother. However, her mother presented no osteopetrosis, but with osteopenia according to BMD, suggesting incomplete penetrance of this disease. This mutation was not detected in her father, younger brother and son. Conclusion Osteopetrosis is a rare bone disease, of which the missense mutations c. 1442C〉T （p. Pro481Leu） in CLCN7 is a novel pathogenic mutation of autosomal dominant osteopetrosis- Ⅱ （ ADO-Ⅱ ）. Our finding would enrich the pathogenic spectrum of ADO-Ⅱ.