Date of Award

2012

Document type

Thesis

Degree Name

PhD (Doctor of Philosophy)

First Supervisor

Professor Gerry McElvaney

Second Supervisor

Dr. Michelle P. Winn

Keywords

Nephritis, Interstitial, Genetics

Abstract

Chronic tubulo-interstitial nephritis (TIN) leads to progressive decline in renal function, involving patho-physiological processes which are poorly understood. Here, six Irish kindreds with familial interstitial nephritis (FIN) are presented. The largest kindred have FIN which is inherited in a dominant fashion and does not associate with the UMOD locus. Genome-wide linkage analysis was performed, and the linkage area was refined with microsatellite markers and haplotype analysis to define the minimal candidate region. Genome-wide linkage analysis yielded a maximum two-point logarithm of odds(LOD) score of 2.62 at marker D1S394 on chromosome 1q. Multipoint parametric LOD score calculation in this family yielded a significant LOD score of 3.598 over a 5 centi-Morgan (cM) span at markers D1S2721, D1S394, RS2317232, RS857819, D1S2635 and RS876537. Fine mapping of this region defined a minimal candidate region of 14.2 Mb with recombination observed at markers D1S25PJL and D1S2844. These data support a locus for FIN at chromosome 1q21-23. The known coding areas within this locus were exhaustively interrogated with standard Sanger sequencing and Whole Exome Capture. No causative mutation was identified in this fashion. It is likely that the responsible variation is due to a “complex rearrangement” or an intronic variation impacting a transcription factor binding site or having an epigenetic effect. Identification of the mutated gene at this locus may illuminate disease mechanisms of interstitial nephritis.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-Share Alike 3.0 License.

File Size

14.3 MB

Comments

Submitted for the Award of Doctor of Philosophy (PhD) to the Royal College of Surgeons, 2012.

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