Bonapace Giuseppe, Moricca Maria Teresa, Talarico Valentina, Graziano Francesca, Pensabene Licia, Miniero Roberto
Department of Pediatrics, Laboratory of Molecular Biology, University Magna Graecia of Catanzaro, Catanzaro, Italy.
Department of Pediatrics, Laboratory of Biochemistry, University Magna Graecia of Catanzaro, Catanzaro, Italy.
Ital J Pediatr. 2014 Nov 20;40:90. doi: 10.1186/s13052-014-0090-6.
Osteopetrosis is a rare genetic disorder characterized by increased bone density due to a defective osteoclast's bone resorption. Three clinical forms can be identified based on severity, age of onset and inheritance: the dominant benign form (ADO), the intermediate form (IRO) and the recessive severe form (ARO). Several genes have been involved in the pathogenesis of these different types of osteopetrosis. Many experimental evidences point out on a specific role for CLCN7, the gene encoding the chloride channel protein subunit alfa and for TCIRG1, the gene encoding an osteoclast specific subunit of the vacuolar proton pump. Mutations in CLCN7 gene have been associated to the complete spectrum of osteopetrosis ranging from ARO to IRO and even to ADO type II. On the other hand, mutations in TCIRG1 gene account for more than 50% of cases of ARO. It is then evident that the malignant osteopetrosis is characterized by a great molecular and clinical heterogeneity often making the final diagnosis difficult to achieve.
We performed a complete clinical, biochemical and molecular analysis by PCR and direct sequencing, of a novel case of osteopetrosis with inconsistent clinical phenotype.
The patient, who cannot be ascribed to any of the ADO, ARO or IRO groups, carried two novel mutations in compound heterozygosis in the CLCN7 gene. The first was the missense mutation c. 948C > T on exon 10 that produces an Arg to Cys change, while the second was the IVS11 + 5G > A splicing mutation that resides on the donor splice site of intron 11 and distrupts the canonical splice site.
Our data a) Demonstrate that the unusual clinical presentation observed in our patient with a mild clinical onset evolving towards a more serious clinical picture, is associated to two novel mutations on CLCN7 gene. b) Support the already described clinical and molecular heterogeneity of the malignant osteopetrosis c) Suggest that, performing a molecular diagnosis of osteopetrosis with inconsistent clinical presentation these two novel mutations have to be first considered.
骨硬化症是一种罕见的遗传性疾病，其特征是由于破骨细胞骨吸收缺陷导致骨密度增加。根据严重程度、发病年龄和遗传方式可识别出三种临床类型：显性良性型（ADO）、中间型（IRO）和隐性严重型（ARO）。几种基因参与了这些不同类型骨硬化症的发病机制。许多实验证据指出编码氯离子通道蛋白亚基α的CLCN7基因以及编码液泡质子泵破骨细胞特异性亚基的TCIRG1基因具有特定作用。CLCN7基因突变与从ARO到IRO甚至到II型ADO的整个骨硬化症谱系相关。另一方面，TCIRG1基因突变占ARO病例的50%以上。因此，恶性骨硬化症的特征是分子和临床高度异质性，这常常使得最终诊断难以实现。
我们通过PCR和直接测序对一例临床表型不一致的骨硬化症新病例进行了全面的临床、生化和分子分析。
该患者不属于ADO、ARO或IRO任何一组，其CLCN7基因存在复合杂合子形式的两个新突变。第一个是外显子10上的错义突变c.948C>T，导致精氨酸变为半胱氨酸，第二个是IVS11+5G>A剪接突变，位于内含子11的供体剪接位点，破坏了经典剪接位点。
我们的数据a）表明，我们的患者临床起病轻微，随后病情逐渐加重，这种不寻常的临床表现与CLCN7基因的两个新突变有关。b）支持已描述的恶性骨硬化症的临床和分子异质性。c）表明，对于临床表现不一致的骨硬化症进行分子诊断时，必须首先考虑这两个新突变。
