title: Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations.
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 We report here the characterization of 25 unpublished patients which has resulted in the identification of 20 novel mutations, including 11 missense mutations, 6 causing premature termination, 1 small deletion and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.
authors: Institute of Biomedical Technologies, National Research Council, 20090 Segrate, Italy.
authors: Alessandra
authors: A
authors: Pangrazio
authors: Michael
authors: M
authors: Pusch
authors: Elena
authors: E
authors: Caldana
authors: Annalisa
authors: A
authors: Frattini
authors: Edoardo
authors: E
authors: Lanino
authors: Parag M
authors: PM
authors: Tamhankar
authors: Shubha
authors: S
authors: Phadke
authors: Antonio Gonzalez Meneses
authors: AG
authors: Lopez
authors: Paul
authors: P
authors: Orchard
authors: Ercan
authors: E
authors: Mihci
authors: Mario
authors: M
authors: Abinun
authors: Michael
authors: M
authors: Wright
authors: Kim
authors: K
authors: Vettenranta
authors: Ivo
authors: I
authors: Bariae
authors: Daniela
authors: D
authors: Melis
authors: Ilhan
authors: I
authors: Tezcan
authors: Clarisse
authors: C
authors: Baumann
authors: Franco
authors: F
authors: Locatelli
authors: Marco
authors: M
authors: Zecca
authors: Edwin
authors: E
authors: Horwitz
authors: Lamia Sfaihi Ben
authors: LS
authors: Mansour
authors: Mirjam
authors: M
authors: Van Roij
authors: Paolo
authors: P
authors: Vezzoni
authors: Anna
authors: A
authors: Villa
authors: Cristina
authors: C
authors: Sobacchi
mesh_terms: D000328:Adult; D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D003460:Crystallization; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D010022:Osteopetrosis / Q000235:genetics* / Q000503:physiopathology*; D010641:Phenotype; D012720:Severity of Illness Index
chemical_list: C097540:CLCN7 protein, human; D018118:Chloride Channels