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

Autor: Alessandra Pangrazio, Paolo Vezzoni, Cristina Sobacchi, Parag M Tamhankar, Clarisse Baumann, Daniela Melis, Edoardo Lanino, Kim Vettenranta, Michael Pusch, Elena Caldana, Edwin M. Horwitz, Franco Locatelli, Annalisa Frattini, Lamia Sfaihi Ben Mansour, Ilhan Tezcan, Ivo Bariae, Anna Villa, Mario Abinun, Paul J. Orchard, Marco Zecca, Antonio González-Meneses López, Michael Wright, Shubha R. Phadke, Ercan Mihci, Mirjam H.H. van Roij
Přispěvatelé: Human genetics, Other Research
Rok vydání: 2010
Předmět:
Zdroj: Human Mutation, 31(1), E1071-E1080. Wiley-Liss Inc.
Human mutation 31 (2010): E1071–E1080. doi:10.1002/humu.21167
info:cnr-pdr/source/autori:Pangrazio A, Pusch M, Caldana E, Frattini A, Lanino E, Tamhankar PM, Phadke S, Lopez AG, Orchard P, Mihci E, Abinun M, Wright M, Vettenranta K, Bariae I, Melis D, Tezcan I, Baumann C, Locatelli F, Zecca M, Horwitz E, Mansour LS, Van Roij M, Vezzoni P, Vil/titolo:Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations/doi:10.1002%2Fhumu.21167/rivista:Human mutation/anno:2010/pagina_da:E1071/pagina_a:E1080/intervallo_pagine:E1071–E1080/volume:31
Pangrazio, A, Pusch, M, Caldana, E, Frattini, A, Lanino, E, Tamhankar, P M, Phadke, S, Lopez, A G M, Orchard, P, Mihci, E, Abinun, M, Wright, M, Vettenranta, K, Bariae, I, Melis, D, Tezcan, I, Baumann, C, Locatelli, F, Zecca, M, Horwitz, E, Ben Mansour, L S, van Roij, M H H, Vezzoni, P, Villa, A & Sobacchi, C 2010, ' Molecular and Clinical Heterogeneity in CLCN7-dependent Osteopetrosis: Report of 20 Novel Mutations ', Human Mutation, vol. 31, no. 1, pp. E1071-E1080 . https://doi.org/10.1002/humu.21167
ISSN: 1098-1004
1059-7794
DOI: 10.1002/humu.21167
Popis: 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 We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and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.
Databáze: OpenAIRE
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