Chloride Channel ClCN7 Mutations Are Responsible for Severe Recessive, Dominant, and Intermediate Osteopetrosis

Abstract

Among 94 osteopetrotic patients presenting with a severe clinical picture and diagnosed early in life, 12 bore mutations in the ClCN7 gene, but only 7 of them had the expected two recessive mutations. The remaining five patients seem to be heterozygous for a ClCN7 mutation, and significant variations were observed in the clinical manifestations of their disease, even within the same family.Introduction: Human osteopetroses are a heterogeneous group of diseases that include both infantile severe, autosomal recessive (ARO) and adult autosomal dominant (ADO) forms. Two genes, Atp6a3 (TCIRG1) and ClCN7, have been shown to be associated with human ARO, the latter of which is also thought to be responsible for ADO-II. However, patients with an intermediate phenotype have been described: the genetic basis of these observances is unknown. Materials and Methods:In this study, we report the clinical and molecular analysis of 94 patients in which a diagnosis of severe osteopetrosis was made within the first 2 years of age. Both TCIRG1 and CLCN7 genes were sequenced in all patients and the molecular findings were correlated to clinical parameters. Results and Conclusions:In 56 of 94 patients with a classical picture of ARO, TCIRG1-dependent recessive mutations were found. In contrast, ClCN7 mutations were found in 12 cases (13%) of severe osteopetrosis, but only 7 of them had two recessive mutations identified: in 6 of these 7 cases, central nervous system manifestations were noted, and these patients had a poor prognosis. The remaining five cases were heterozygous for a ClCN7 mutation,

Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations

“…This form is frequently lethal in early life, despite haematological reconstitution by haematopoietic stem cell transplantation (HSCT). Few reports describe this subgroup of ARO patients, since in addition to the cases reported by our group (8 patients in Frattini et al, 2003 and1 in Shin et al, 2004), only 6 cases have been published (Cleiren et al, 2001;Kornak et al, 2001;Lam et al, 2007 ;Besbas et al, 2009). CLCN7-associated IAO is an elusive entity; it is generally classified as a form of osteopetrosis milder than ARO, identified in childhood due to fractures after minor trauma, characteristic skeletal radiographic changes found accidentally, mild anaemia and occasional visual impairment.…”

“…CLCN7-dependent ARO is usually diagnosed at birth or early in infancy due to generalized osteosclerosis and severe haematological deficits; primary neurological defects, such as cerebral and retinal atrophy, are often present and are displayed also by the knockout mouse (Kornak et al, 2001;Frattini et al, 2003;Kasper et al, 2005). This form is frequently lethal in early life, despite haematological reconstitution by haematopoietic stem cell transplantation (HSCT).…”

“…CLCN7-associated IAO is an elusive entity; it is generally classified as a form of osteopetrosis milder than ARO, identified in childhood due to fractures after minor trauma, characteristic skeletal radiographic changes found accidentally, mild anaemia and occasional visual impairment. The affected individuals are expected to reach adulthood, in contrast to ARO patients (Campos-Xavier et al, 2003;Frattini et al, 2003).…”

“…Although there is some overlap between the clinical severity of IAO and that of ADO II, the dominant means of transmission and the presence of a single mutated allele clearly distinguish this latter form from IAO (Cleiren et al, 2001;Frattini et al, 2003;Del Fattore et al, 2006;Waguespack et al, 2007). The reduced penetrance of the dominant CLCN7 mutations in ADO II has long been recognized, since members of the same affected family with identical mutations in the ClCN7 gene are often symptomatic.…”

SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity

“…(1,(5)(6)(7)(8)(9)(10) The SNX10 gene was amplified using primers and conditions kindly provided by Aker and colleagues (Hebrew University Medical Center, Jerusalem). The mutation nomenclature conforms to www.hgvs.org/mutnomen.…”