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Sindhuri Prakash
MD/PhD Program
B.S. 2008, Fairleigh Dickinson University, Madison, NJ

Thesis Advisor: Ali G. Gharavi, M.D.
Professor of Medicine, Columbia University

Thesis Advisor on record: Elizabeth Raveche, Ph.D.
Adjunct Professor, Department of Pathology

Thesis Advisor on record: Christine Rohowsky Kochan, Ph.D.
Professor, Department of Neurology and Neurosciences

Wednesday, May 13, 2015
10:00 AM, Cancer Center G level Auditorium, Room G-1196


IgA nephropathy (IgAN) is the most commonly diagnosed primary glomerulonephritis worldwide. 30-50% of cases progress to end stage renal failure within 20 years. Around 10% of these cases are familial, with pedigrees following an autosomal dominant pattern with incomplete penetrance. Genetic factors have long been known to be important in the pathogenesis of IgAN. Three genome wide association studies (GWAS) have uncovered 15 disease loci that only explain 6-8% of disease variance. Several linkage studies have identified several significant and suggestive loci on Chr. 6q22-23, 3p21-25, 17q12, uncovering high degree of genetic heterogeneity, without an identified gene. This doctoral thesis work describes the first gene identification for IgAN.
To tackle the problems of genetic heterogeneity and incomplete penetrance, 10 IgAN families were exome sequenced to find genes. This culminated in the discovery of a loss of function segregating variant in GALNT14, a gene homologous to one of the glycosyltransferases participating in the IgA1 biosynthetic pathway. Additionally, eight independent variants in this gene were found, establishing genetic causality. Loss of function mutations in GALNT14 leads to increased total IgA levels, but does not affect IgA1 or galactose deficient IgA1 levels.
Species conservation of the GALNT14 protein justified the use of a murine model to determine if GALNT14 may be participating in IgAN pathogenesis through alternative pathways. Aged Galnt14 knock-out mice (8 and 12 months) have increased IgA deposition in their kidney mesangium when compared to controls without a concomitant increase in serum IgA levels. This led to the hypothesis that disrupting the intestinal epithelial barrier can precipitate the disease by allowing the translocation of commensal bacteria into the systemic circulation. To test this hypothesis, mice were challenged with dextran sodium sulfate, a direct toxin to intestinal epithelial cells. GALNT14 knock-out mice have increased IgA deposition in the kidney mesangium when compared to controls, but do not have a concomitant increase in serum IgA levels. Collectively, this work has culminated in the identification of GALNT14 as a causal gene for IgAN, which does not affect IgA levels, but may play a role in mucosal epithelial barrier integrity.

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