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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: Report of 20 novel mutations
Human Mutation, Volume 31, No. 1, Year 2010
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Description
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 We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and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.
Authors & Co-Authors
Pangrazio, Alessandra
Italy, Rome
Consiglio Nazionale Delle Ricerche
Italy, Rozzano
Humanitas Research Hospital
Pusch, Michael
Italy, Rome
Consiglio Nazionale Delle Ricerche
Caldana, Elena
Italy, Rome
Consiglio Nazionale Delle Ricerche
Italy, Rozzano
Humanitas Research Hospital
Frattini, Annalisa
Italy, Rome
Consiglio Nazionale Delle Ricerche
Lanino, Edoardo
Italy, Genoa
Istituto Giannina Gaslini
Tamhankar, Parag Mohan
India, Lucknow
Sanjay Gandhi Postgraduate Institute of Medical Sciences
Phadke, Shubha R.
India, Lucknow
Sanjay Gandhi Postgraduate Institute of Medical Sciences
Lopez, Antonio Gonzalez Meneses
Spain, Sevilla
Hospital Universitario Virgen Del Rocío
Orchard, Paul J.
United States, Minneapolis
University of Minnesota Twin Cities
Mıhçı, Ercan
Turkey, Antalya
Akdeniz Üniversitesi
Abinun, Mario A.
United Kingdom, Newcastle
Newcastle University
Wright, Michael J.
United Kingdom, Newcastle
Northern Genetics Service
Vettenranta, Kim
Finland, Tampere
Tampere University
Bariæ, Ivo
Croatia, Zagreb
Kbc Zagreb
Melis, Daniela
Italy, Naples
Università Degli Studi Di Napoli Federico Ii
Tezcan, Ilhan
Turkey, Ankara
Hacettepe Üniversitesi
Baumann, Clarisse
France, Paris
Hôpital Robert-debré Ap-hp
Locatelli, Franco
Italy, Pavia
Università Degli Studi Di Pavia
Zecca, Marco
Italy, Pavia
Università Degli Studi Di Pavia
Horwitz, Edwin
United States, Philadelphia
The Children's Hospital of Philadelphia
Mansour, Lamia Sfaihi Ben
Tunisia, Sfax
Chu Hedi-chaker
Van Roij, Mirjam
Netherlands, Amsterdam
Amsterdam Umc - Vrije Universiteit Amsterdam
Vezzoni, Paolo
Italy, Rome
Consiglio Nazionale Delle Ricerche
Italy, Rozzano
Humanitas Research Hospital
Villa, Anna
Italy, Rome
Consiglio Nazionale Delle Ricerche
Italy, Rozzano
Humanitas Research Hospital
Sobacchi, Cristina
Italy, Rome
Consiglio Nazionale Delle Ricerche
Italy, Rozzano
Humanitas Research Hospital
Statistics
Citations: 84
Authors: 25
Affiliations: 18
Identifiers
Doi:
10.1002/humu.21167
ISSN:
10597794
Research Areas
Cancer
Genetics And Genomics
Maternal And Child Health
Study Design
Cohort Study