title: Genotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis.
abstract: 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.
authors.affiliation: Istituto Dermopatico dell'Immacolata, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Taranta
authors.forename: Silvia
authors.initials: S
authors.lastname: Migliaccio
authors.forename: Irene
authors.initials: I
authors.lastname: Recchia
authors.forename: Maurizio
authors.initials: M
authors.lastname: Caniglia
authors.forename: Matteo
authors.initials: M
authors.lastname: Luciani
authors.forename: Giulio
authors.initials: G
authors.lastname: De Rossi
authors.forename: Carlo
authors.initials: C
authors.lastname: Dionisi-Vici
authors.forename: Rita M
authors.initials: RM
authors.lastname: Pinto
authors.forename: Paola
authors.initials: P
authors.lastname: Francalanci
authors.forename: Renata
authors.initials: R
authors.lastname: Boldrini
authors.forename: Edoardo
authors.initials: E
authors.lastname: Lanino
authors.forename: Giorgio
authors.initials: G
authors.lastname: Dini
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Morreale
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Ralston
authors.forename: Anna
authors.initials: A
authors.lastname: Villa
authors.forename: Paolo
authors.initials: P
authors.lastname: Vezzoni
authors.forename: Domenico
authors.initials: D
authors.lastname: Del Principe
authors.forename: Flaminia
authors.initials: F
authors.lastname: Cassiani
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Palumbo
authors.forename: Anna
authors.initials: A
authors.lastname: Teti
mesh_terms: D000135:Acid Phosphatase / Q000096:biosynthesis; D001706:Biopsy; D016026:Bone Marrow Transplantation; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology; D002478:Cells, Cultured; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005091:Exons; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D005838:Genotype; D006801:Humans; D007085:Ilium / Q000000981:diagnostic imaging / Q000473:pathology; D007223:Infant; D007231:Infant, Newborn; D007438:Introns; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D009154:Mutation; D010010:Osteoclasts / Q000201:enzymology / Q000473:pathology*; D010022:Osteopetrosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D010641:Phenotype; D021122:Protein Subunits / Q000235:genetics; D011859:Radiography; D000071681:Tartrate-Resistant Acid Phosphatase; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics* / Q000378:metabolism
chemical_list: D007527:Isoenzymes; D021122:Protein Subunits; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D025262:Vacuolar Proton-Translocating ATPases