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Title: Genetic and molecular investigations into Amelogenesis Imperfecta and Nephrocalcinosis
Author: Jaureguiberry, G.
ISNI:       0000 0004 5358 3369
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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Background Calcium has a critical role in cell physiology and needs a tight regulation to maintain an adequate activity and movement. This exquisite regulation involves cellular, paracellular and interstitial systems. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood. Methods We investigated 16 families with a total of 25 patients, who exhibited nephrocalcinosis and amelogenesis imperfecta. To identify the genetic defect we performed linkage analysis, exome capture, next generation and Sanger sequencing. Human dissected kidney was used to perform expression studies. Patient gingival fibroblasts were cultured in vitro and used for cell biological studies. Patients’ spot urines were analysed by Proton-NMR spectroscopy. Results All patients with ectopic calcifications in teeth, gingiva and kidney exhibited biallelic mutations in FAM20A. A total of 20 different mutations were identified and all of them segregated with the disease. Expression of FAM20A was detected in kidney, including the interstitium. Patient fibroblasts showed an increased content of chondroitin sulfate and extracellular free ionised calcium concentrations. Calcification was induced in patient gingival fibroblasts and reverted by overexpressing FAM20A. Urine samples from patients exhibited reduced citrate and increased acetate concentrations. Conclusions The combination of nephrocalcinosis without hypercalcemia or hypercalciuria, amelogenesis imperfecta and other ectopic calcifications are part of an autosomal recessive disorder caused by mutations in FAM20A. The inhibitory effect of FAM20A on glycosaminoglycans is essential to maintain interstitial free ionised calcium in equilibrium, suggesting a new concept in the understanding of nephrocalcinosis and the importance of the interstitial buffer system in calcium homeostasis and biomineralization.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available