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

Abstract

ABSTRACT:The "Osteopetroses" are genetic diseases whose clinical picture is caused by a defect in bone resorption by osteoclasts. Three main forms can be distinguished on the basis of severity, age of onset and means of inheritance: the dominant benign, the intermediate and the recessive severe form. While several genes have been involved in the pathogenesis of the different types of osteopetroses, the CLCN7 gene has drawn the attention of many researchers, as mutations within this gene are associated with very different phenotypes. We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and 2 putative splice site defects. Careful analysis of clinical and molecular data led us to several conclusions. First, intermediate osteopetrosis is not homogeneous, since it can comprise both severe dominant forms with an early onset and recessive ones without central nervous system involvement. Second, the appropriateness of haematopoietic stem cell transplantation in CLCN7-dependent ARO patients has to be carefully evaluated and exhaustive CNS examination is strongly suggested, as transplantation can almost completely cure the disease in situations where no primary neurological symptoms are present. Finally, the analysis of this largest cohort of CLCN7-dependent ARO patients together with some ADO II families allowed us to draw preliminary genotype-phenotype correlations suggesting that haploinsufficiency is not the mechanism causing ADO II. The availability of biochemical assays to characterize ClC-7 function will help to confirm this hypothesis.

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

“…Thereby, the scientific basis was established for experimental treatment of the severe clinical (malignant) forms of ARO with bone marrow transplantation in children (88,89) in the early 1980s. This is now an established treatment modality (90,91). However, no specific pharmacological therapy for ADO is currently available.…”

“…In addition, the patients and mice with complete loss of function or expression of ClC-7 are known to show primary neurological issues (49,91,99); however, analyses of the ADO patients, which, based on gene doses, have 25% residual ClC-7 activity remaining, have not shown any primary neurological phenomena (14,20,91), indicating that the neurological problems only arise when ClC-7 is completely inactive or absent, and this level of inhibition of ClC-7 is not expected with small-molecule inhibitors.…”

Osteopetroses, emphasizing potential approaches to treatment

“…The only gene implicated so far in dominant forms of osteopetrosis is the CLCN7, in which various types of mutations cause ADO2 by a dominant negative mechanism (8)(9)(10)(11)(12)(63)(64)(65)(66)(67)(68) 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 15 associates with the Ostm1 protein, which is essential for its correct localization (53). Through its stoichiometry of 2 chlorides against 1 proton, the antiporter releases negative charges into the acidic vesicles and the Howship lacuna, which balance the transport of positive charges by the V-H * ATPase (1).…”

“…Mutations in the gene coding for carbonic anhydrase tend instead to result in a more moderate phenotype, but with cognitive disabilities, as well as other morbidities (6). The dominant form of osteopetrosis, due to dominant negative mutations in the CLCN7 gene, can result in mild, moderate, but also severe disease, although with less infirmities than autosomal recessive forms (7)(8)(9)(10)(11)(12).…”

Differentially expressed genes in autosomal dominant osteopetrosis type II osteoclasts reveal known and novel pathways for osteoclast biology

“…12,13 Asymptomatic forms or healthy carriers are not exceptional. 8,14 Patients have an increased number of osteoclasts; however, these are unable to form ruffled borders or to resorb bone efficiently. 15 The CLCN7 gene encodes a chloride channel that is a member of the voltage-gated chloride channels family, 3,16 and has Cl À /H þ exchanger properties.…”