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Genotype-phenotype relationship in human ATP6i-dependent autosomal recessive osteopetrosis
Anna Taranta1, Silvia Migliaccio, Irene Recchia
1Istituto Dermopatico dell'Immacolata, Rome, Italy.
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.
Insights
Autosomal-recessive osteopetrosis is a severe genetic disorder caused by osteoclast dysfunction. Mutations in the ATP6i gene lead to a lack of the a3 subunit, impairing bone resorption and causing disease.
Area of Science:
- Genetics
- Cell Biology
- Bone Biology
Background:
- Autosomal-recessive osteopetrosis is a severe genetic disorder resulting from osteoclast failure.
- Mutations in the ATP6i gene, encoding the V-ATPase a3 subunit, are found in about 50% of patients.
Purpose of the Study:
- To investigate the role of ATP6i gene mutations in autosomal-recessive osteopetrosis.
- To characterize the osteoclast dysfunction and potential therapeutic strategies.
Main Methods:
- Genetic analysis to identify ATP6i mutations in patients.
- Bone biopsy analysis to examine osteoclast morphology and function.
- In vitro studies of patient-derived osteoclasts.
- Evaluation of bone marrow transplantation efficacy.
Main Results:
- Identified inactivating ATP6i mutations in four patients, three novel.
- Observed characteristic clinical features including macrocephaly and optic nerve alteration.
- Bone biopsies and in vitro studies revealed a3-negative osteoclasts with impaired bone resorption.
- Bone marrow transplantation successfully restored a3 subunit expression in post-transplant osteoclasts.
Conclusions:
- Inactivating ATP6i mutations are a significant cause of autosomal-recessive osteopetrosis.
- Osteoclast-specific a3 subunit deficiency leads to impaired bone resorption and characteristic disease phenotypes.
- Bone marrow transplantation is an effective therapy for restoring osteoclast function.