Autosomal dominant osteopetrosis associated with renal tubular acidosis is due to a CLCN7 mutation

Abstract

The aim of this study was to identify the causative mutation in a family with an unusual presentation of autosomal dominant osteopetrosis (OPT), proximal renal tubular acidosis (RTA), renal stones, epilepsy, and blindness, a combination of features not previously reported. We undertook exome sequencing of one affected and one unaffected family member, followed by targeted analysis of known candidate genes to identify the causative mutation. This identified a missense mutation (c.643G>A; p.Gly215Arg) in the gene encoding the chloride/proton antiporter 7 (gene CLCN7, protein CLC‐7), which was confirmed by amplification refractory mutation system (ARMS)‐PCR, and to be present in the three available patients. CLC‐7 mutations are known to cause autosomal dominant OPT type 2, also called Albers–Schonberg disease, which is characterized by osteosclerosis, predominantly of the spine, pelvis and skull base, resulting in bone fragility and fractures. Albers–Schonberg disease is not reported to be associated with RTA, but autosomal recessive OPT type 3 (OPTB3) with RTA is associated with carbonic anhydrase type 2 (CA2) mutations. No mutations were detected in CA2 or any other genes known to cause proximal RTA. Neither CLCN7 nor CA2 mutations have previously been reported to be associated with renal stones or epilepsy. Thus, we identified a CLCN7 mutation in a family with autosomal dominant osteopetrosis, RTA, renal stones, epilepsy, and blindness. © 2016 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

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.…”

The Role of the Lysosomal Cl−/H+ Antiporter ClC-7 in Osteopetrosis and Neurodegeneration

“…ClC-7 expression has also been detected in the luminal membrane of the choroid plexus [17], but its physiological role in that context is still unclear. Intriguingly, CLCN7 has been identified as the causative gene in a quite unique phenotype combining osteopetrosis, renal tubule acidosis, renal stones, epilepsy, and blindness [18]. Moreover, ClC-7 has been implicated in Alzheimer disease [19].…”