ABCC6 and CKD: The Phenotypic Expansion of Pseudoxanthoma Elasticum
- Genetic Diseases: Tubulopathies
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
- Schott, Clara, Western University Schulich School of Medicine & Dentistry, London, Ontario, Canada
- Baker, Cadence, London Health Sciences Centre, London, Ontario, Canada
- Colaiacovo, Samantha, London Health Sciences Centre, London, Ontario, Canada
- Connaughton, Dervla M., Western University Schulich School of Medicine & Dentistry, London, Ontario, Canada
Adenosine triphosphate (ATP) Binding Cassette Subfamily C Member 6 (ABCC6) is a transporter nucleotide that mediates cellular efflux of ATP, which is hypothesized to prevent calcification. In chronic kidney disease (CKD) patients, vascular calcification is prevalent but not completely understood. Monogenic cause occurs in 10% of CKD patients, however monogenic causes of vascular calcification in CKD have yet to be identified. Both recessive and dominant variants in ABCC6 are known to cause Pseudoxanthoma Elasticum (PXE), a heritable disorder characterized by the accumulation calcium deposits and subsequent vascular calcification involving elastic fibers in the skin, eyes, and cardiovascular system. Data suggests PXE is associated with nephrolithiasis and nephrocalcinosis, with reports also suggesting higher prevalence of end-stage kidney disease (ESKD), glomerulonephritis, and renovascular hypertension. This is hypothesized to be secondary to elastic fiber fragmentation and mineralization in renal arteries. In addition, knockout mice models in ABCC6 developed calcification in the blood vessels, prominently in the renal cortex, in association with papillary calcification.
To identify monogenic kidney disease associated with vascular calcification phenotype, we performed whole exome sequencing (WES) in 94 families with CKD, looking for pathogenic variants in the gene ABCC6.
We identified 2 heterozygous, loss of function variants in ABCC6 in 2 families with CKD of unknown etiology (c.1999delG p.A667fs and c.C3421T:p.R1141X). No formal diagnosis of PXE was established prior to analysis. Affected individuals were reviewed post exome analysis and were found to exhibit a broad spectrum of extra-renal phenotypes including eye and skin pathology, and severe peripheral vascular disease. Renal phenotype included a history of kidney stones along with CKD of unknown etiology progressing to ESKD in multiple family members.
We identified loss of function variants in ABCC6 in two families with CKD by reverse phenotyping for PXE. This report suggests the need for phenotype expansion of PXE to include CKD. Further work is required to establish the exact role in disease pathogenesis but preliminary data suggests that heterozygous variants in ABCC6 may lead to multi-system vascular calcification disease, also affecting the kidney.