Genetic Analysis ofCLCN7in an Old Female Patient with Type II Autosomal Dominant Osteopetrosis

Abstract

BackgroundType II autosomal dominant osteopetrosis (ADO II) is a rare genetically heterogeneous disorder characterized by osteosclerosis and increased bone mass, predominantly involving spine, pelvis, and skull. It is closely related to functional defect of osteoclasts caused by chloride voltage-gated channel 7 (CLCN7) gene mutations. In this study, we aimed to identify the pathogenic mutation in a Korean patient with ADO II using whole exome sequencing.MethodsWe evaluated the clinical, biochemical, and radiographic analysis of a 68-year-old woman with ADO II. We also performed whole exome sequencing to identify pathogenic mutation of a rare genetic disorder of the skeleton. Moreover, a polymorphism phenotyping program, Polymorphism Phenotyping v2 (PolyPhen-2), was used to assess the effect of the identified mutation on protein function.ResultsWhole exome sequencing using peripheral leukocytes revealed a heterozygous c.296A>G missense mutation in the CLCN7 gene. The mutation was also confirmed using Sanger sequencing. The mutation c.296A>G was regarded to have a pathogenic effect by PolyPhen-2 software.ConclusionWe detect a heterozygous mutation in CLCN7 gene of a patient with ADO II, which is the first report in Korea. Our present findings suggest that symptoms and signs of ADO II patient having a c.296A>G mutation in CLCN7 may appear at a very late age. The present study would also enrich the database of CLCN7 mutations and improve our understanding of ADO II.

Magnetic resonance findings in a Cavalier King Charles spaniel with osteopetrosis, Chiari‐like malformation and syringomyelia

“…1 There are at least 10 genes identified in this disease process including TCIRG1, OSTEM1, CLCN7, RANK and RANKL. [23][24][25][26][27] In OP, the relative interactions between the normal processes of skull growth are altered. 1 2 Normal bone growth is regulated by a balance between bone formation by osteoblasts and bone resorption by osteoclasts.…”

“…1 2 Gene mutations cause failure of the physiological resorptive process and hence a remodelling imbalance. [23][24][25][26][27] The exact pathophysiological mechanism is unknown; however, deficiency of carbonic anhydrase II was noted in osteoclasts of affected human patients. 24 Carbonic anhydrases catalyse the formation of carbonic acid from carbon dioxide and water.…”

“…OP is a rare and hereditary skeletal disease that was first described in 1904 by the German radiologist Albers‐Schönberg 1. There are at least 10 genes identified in this disease process including TCIRG1, OSTEM1, CLCN7, RANK and RANKL 23–27. In OP, the relative interactions between the normal processes of skull growth are altered 1 2.…”

“…Normal bone growth is regulated by a balance between bone formation by osteoblasts and bone resorption by osteoclasts 1 2. Gene mutations cause failure of the physiological resorptive process and hence a remodelling imbalance 23–27. The exact pathophysiological mechanism is unknown; however, deficiency of carbonic anhydrase II was noted in osteoclasts of affected human patients 24.…”