Patel, V; (2018) Proteomic studies into the pathogenesis of enamel renal syndrome. Doctoral thesis (Ph.D), UCL (University College London).

Abstract

Background Enamel Renal Syndrome is an autosomal recessive disorder that is characterised by nephrocalcinosis and amelogenesis imperfecta where the causative gene is FAM20A. Unlike most cases of nephrocalcinosis where hypercalciuria is its instrumental cause, patients with ERS have normocalciuria, suggesting an atypical mechanism in calcium handling by the kidneys. Methods Detection of recombinant FAM20A was performed on HeLa cells and its culture media by Western analysis. Plasma and gingival fibroblasts were used for the detection of FAM20A in control and ERS samples by two-dimensional gel electrophoresis. Human milk was utilised for the quantitation of FAM20A using both shotgun and targeted proteomics approach. Mouse kidneys were used for differential protein expression and functional proteomic analysis to help understand how the absence of FAM20A can severely impact calcium homeostasis. Results A low amount of FAM20A was detected in human milk. Results from plasma samples and gingival fibroblasts were inconclusive. Differential protein expression profiling of kidneys revealed S100 calcium-binding protein A9 to be 2.9 fold up-regulated in the Fam20a knockout mouse. This protein is a major determinant of arterial calcification. Functional analysis indicated disturbed calcium-regulation mediated by mitochondria and peroxisomes in the absence of Fam20a. Conclusion The removal of FAM20A triggers a disruptive ripple in the finely tuned intricate pathway of proteins all entangled to regulate calcium homeostasis; a consequence of which leads to ectopic calcification within the interstitium.

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