TY - JOUR
T1 - Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis
T2 - Report of 20 novel mutations
AU - Pangrazio, Alessandra
AU - Pusch, Michael
AU - Caldana, Elena
AU - Frattini, Annalisa
AU - Lanino, Edoardo
AU - Tamhankar, Parag M.
AU - Phadke, Shubha
AU - Lopez, Antonio Gonzalez Meneses
AU - Orchard, Paul
AU - Mihci, Ercan
AU - Abinun, Mario
AU - Wright, Michael
AU - Vettenranta, Kim
AU - Bariæ, Ivo
AU - Melis, Daniela
AU - Tezcan, Ilhan
AU - Baumann, Clarisse
AU - Locatelli, Franco
AU - Zecca, Marco
AU - Horwitz, Edwin
AU - Mansour, Lamia Sfaihi Ben
AU - Van Roij, Mirjam
AU - Vezzoni, Paolo
AU - Villa, Anna
AU - Sobacchi, Cristina
PY - 2010/1
Y1 - 2010/1
N2 - 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 We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and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.
AB - 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.
KW - Chloride
KW - CNS defects
KW - Osteopetrosis
KW - Transplantation
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U2 - 10.1002/humu.21167
DO - 10.1002/humu.21167
M3 - Article
C2 - 19953639
AN - SCOPUS:74049126057
VL - 31
JO - Human Mutation
JF - Human Mutation
SN - 1059-7794
IS - 1
ER -