Genotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis

Anna Taranta, Silvia Migliaccio, Irene Recchia, Maurizio Caniglia, Matteo Luciani, Giulio De Rossi, Carlo Dionisi-Vici, Rita M Pinto, Paola Francalanci, Renata Boldrini, Edoardo Lanino, Giorgio Dini, Giuseppe Morreale, Stuart H Ralston, Anna Villa, Paolo Vezzoni, Domenico Del Principe, Flaminia Cassiani, Giuseppe Palumbo, Anna Teti

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

Autosomal-recessive osteopetrosis is a severe genetic disease caused by osteoclast failure. Approximately 50% of the patients harbor mutations of the ATP6i gene, encoding for the osteoclast-specific a3 subunit of V-ATPase. We found inactivating ATP6i mutations in four patients, and three of these were novel. Patients shared macrocephaly, growth retardation and optic nerve alteration, osteosclerotic and endobone patterns, and high alkaline phosphatase and parathyroid hormone levels. Bone biopsies revealed primary spongiosa lined with active osteoblasts and high numbers of tartrate-resistant acid phosphatase (TRAP)-positive, a3 subunit-negative, morphologically unremarkable osteoclasts, some of which located in shallow Howship lacunae. Scarce hematopoietic cells and abundant fibrous tissue containing TRAP-positive putative osteoclast precursors were noted. In vitro osteoclasts were a3-negative, morphologically normal, with prominent clear zones and actin rings, and TRAP activity more elevated than in control patients. Podosomes, alphaVbeta3 receptor, c-Src, and PYK2 were unremarkable. Consistent with the finding in the bone biopsies, these cells excavated pits faintly stained with toluidine blue, indicating inefficient bone resorption. Bone marrow transplantation was successful in all patients, and posttransplant osteoclasts showed rescue of a3 subunit immunoreactivity.
Original languageEnglish
Pages (from-to)57-68
Number of pages12
JournalThe American Journal of Pathology
Issue number1
Publication statusPublished - Jan 2003


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