Department of Human Genetics, McGill University and Genome Quebec Innovation Centre, Canada.
Hum Mutat. 2011 Oct;32(10):1114-7. doi: 10.1002/humu.21546. Epub 2011 Sep 9.
Hajdu-Cheney syndrome (HCS) is a rare genetic disorder whose hallmark is acro-osteolysis, shortening of terminal phalanges, and generalized osteoporosis. We assembled a cohort of seven families with the condition and performed whole exome resequencing on a selected set of affected patients. One protein-coding gene, NOTCH2, carried heterozygous truncating variants in all patients and their affected family members. Our results replicate recently published studies of HCS and further support this as the causal gene for the disorder. In total, we identified five novel and one previously reported mutation, all clustered near the carboxyl terminus of the gene, suggesting an allele specific genotype-phenotype effect since other mutations in NOTCH2 have been reported to cause a form of Alagille syndrome. Notch-mediated signaling is known to play a role in bone metabolism. Our results support a potential therapeutic role for Notch pathways in treatment of osteoporosis.
哈杰-切尼综合征（HCS）是一种罕见的遗传性疾病，其特征是肢端溶骨、末端指骨缩短和全身性骨质疏松症。我们收集了一组七个患有这种疾病的家庭，并对一组选定的受影响患者进行了全外显子组重测序。一种名为 NOTCH2 的蛋白编码基因在所有患者及其受影响的家族成员中均携带杂合截断变异。我们的结果复制了最近发表的 HCS 研究，并进一步支持了这是该疾病的致病基因。总的来说，我们鉴定了五个新的突变和一个以前报道的突变，都聚集在基因的羧基末端附近，这表明存在等位基因特异性的基因型-表型效应，因为 NOTCH2 中的其他突变已被报道会导致一种 Alagille 综合征。已知 Notch 介导的信号转导在骨骼代谢中发挥作用。我们的结果支持 Notch 途径在骨质疏松症治疗中的潜在治疗作用。
