Clinical, genetic, and cellular analysis of 49 osteopetrotic patients: implications for diagnosis and treatment

• Published in: Journal of medical genetics 2006-04, Vol.43 (4), p.315-325
• Main Authors: Del Fattore, A, Peruzzi, B, Rucci, N, Recchia, I, Cappariello, A, Longo, M, Fortunati, D, Ballanti, P, Iacobini, M, Luciani, M, Devito, R, Pinto, R, Caniglia, M, Lanino, E, Messina, C, Cesaro, S, Letizia, C, Bianchini, G, Fryssira, H, Grabowski, P, Shaw, N, Bishop, N, Hughes, D, Kapur, R P, Datta, H K, Taranta, A, Fornari, R, Migliaccio, S, Teti, A
• Format: Article
• Language: English
• Subjects: 5-(N-ethyl-N-iso-propyl)-amiloride; Acidification; ADO; Adolescent; Adult; Alkaline Phosphatase - blood; ARO; ATP6i/TCIRG1 gene; autosomal dominant osteopetrosis; autosomal recessive osteopetrosis; BALP; Biological and medical sciences; Biopsy; bone alkaline phosphatase; Bone Resorption - metabolism; Bone Resorption - pathology; CA II; carbonic anhydrase II; Cardiology. Vascular system; Child; Child, Preschool; Chloride Channels - chemistry; Chloride Channels - genetics; ClCN7 gene; Deoxyribonucleic acid; DNA; EIPA; Female; General aspects. Genetic counseling; Genes; Genotype; Histology; Humans; Hydrogen-Ion Concentration; intermediate autosomal recessive osteopetrosis; IRO; M-CSF; macrophage colony stimulating factor; Male; Medical genetics; Medical sciences; Morphology; Mutation; Ob.S/BS; Oc.S/BS; Original; OSCA; osteoblast; osteoblast surface/bone surface; osteocalcin; Osteocalcin - blood; osteoclast; osteoclast surface/bone surface; Osteoclasts - pathology; Osteoclasts - physiology; osteopetrosis; Osteopetrosis - diagnosis; Osteopetrosis - genetics; Osteopetrosis - therapy; parathyroid hormone; Phosphoric Monoester Hydrolases - blood; Proteins; PTH; RANKL; receptor activator of NF-κB ligand; Sodium-Hydrogen Exchangers - physiology; tartrate resistant acid phosphatase; TRAcP; V-H+ATPase; vacuolar H+ATPase; Vacuolar Proton-Translocating ATPases - genetics
• ISSN: 0022-2593; 1468-6244; 1468-6244
• DOI: 10.1136/jmg.2005.036673

Background: Osteopetrosis, a genetic disease characterised by osteoclast failure, is classified into three forms: infantile malignant autosomal recessive osteopetrosis (ARO), intermediate autosomal recessive osteopetrosis (IRO), and autosomal dominant osteopetrosis (ADO). Methods: We studied 49 patients, 21 with ARO, one with IRO, and 27 with type II ADO (ADO II). Results: Most ARO patients bore known or novel (one case) ATP6i (TCIRG1) gene mutations. Six ADO II patients had no mutations in ClCN7, the only so far recognised gene implicated, suggesting involvement of yet unknown genes. Identical ClCN7 mutations produced differing phenotypes with variable degrees of severity. In ADO II, serum tartrate resistant acid phosphatase was always elevated. Bone alkaline phosphatase (BALP) was generally low, but osteocalcin was high, suggesting perturbed osteoblast differentiation or function. In contrast, BALP was high in ARO patients. Elevated osteoclast surface/bone surface was noted in biopsies from most ARO patients. Cases with high osteoclasts also showed increased osteoblast surface/bone surface. ARO osteoclasts were morphologically normal, with unaltered formation rates, intracellular pH handling, and response to acidification. Their resorption activity was greatly reduced, but not abolished. In control osteoclasts, all resorption activity was abolished by combined inhibition of proton pumping and sodium/proton antiport. Conclusions: These findings provide a rationale for novel therapies targeting pH handling mechanisms in osteoclasts and their microenvironment.