Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of renal and liver related perinatal and neonatal death. ARPKD is presented as a gross enlargement of the kidneys due to the presence of multiple fluid filled cysts. When renal cysts present in the absence of additional abnormalities, ARPKD is often attributed to mutations in the PKHD1 gene which encodes the protein fibrocystin.
However many syndromes also present with renal cyst disease as one of a number of clinical characteristics, including Joubert syndrome, Bardet-Biedl syndrome, and Meckel-Gruber syndrome. These syndromes are all classed as ciliopathies which is a term describing diseases with structural or functional defects in the cell‟s primary cilia, a sensory organelle that coordinates a large number of cellular signalling pathways.
We have identified an ovine model of polycystic kidney disease and have set up specific breeding and determined the inheritance of this disease to be recessive. Ovine SNP50 BeadChips, developed by Illumina in conjunction with the International Sheep Genomics Consortia (www.sheephapmap.org), were hybridized with DNA from affected sheep. Three candidate regions were identified by homozygosity mapping, one on each of chromosomes 4, 9, and 11.
In the region of concordant homozygosity on chromosome 9 we located the gene TMEM67 which is known to play a role in many ciliopathies. Upon sequencing of this gene two sequence variants were identified I638N and I644S. Bioinformatic analysis of both of these polymorphisms was unable to rule them out as the causative mutations in these sheep.
This study aimed to characterise the PKD sheep both phenotypically and genetically. The approach of using the SNP50 bead chip to identify regions of interest was crucial to the discovery of the sequence variants. At this time all the evidence supports the hypothesis that I638N and I644S are causative.
