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Molecular and clinical heterogeneity in CLCN7‐dependent osteopetrosis: report of 20 novel mutations
Author(s) -
Pangrazio Alessandra,
Pusch Michael,
Caldana Elena,
Frattini Annalisa,
Lanino Edoardo,
Tamhankar Parag M,
Phadke Shubha,
Lopez Antonio Gonzalez Meneses,
Orchard Paul,
Mihci Ercan,
Abinun Mario,
Wright Michael,
Vettenranta Kim,
Bariæ Ivo,
Melis Daniela,
Tezcan Ilhan,
Baumann Clarisse,
Locatelli Franco,
Zecca Marco,
Horwitz Edwin,
Mansour Lamia Sfaihi Ben,
Van Roij Mirjam,
Vezzoni Paolo,
Villa Anna,
Sobacchi Cristina
Publication year - 2010
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21167
Subject(s) - osteopetrosis , biology , haploinsufficiency , missense mutation , genetics , genetic heterogeneity , transplantation , phenotype , mutation , loss function , gene , immunology , medicine
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 We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and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. © 2009 Wiley‐Liss, Inc.