Multi-omic analyses in Abyssinian cats with primary renal amyloid deposits

Abstract

The amyloidoses constitute a group of diseases occurring in humans and animals that are characterized by abnormal deposits of aggregated proteins in organs, affecting their structure and function. In the Abyssinian cat breed, a familial form of renal amyloidosis has been described. In this study, multi-omics analyses were applied and integrated to explore some aspects of the unknown pathogenetic processes in cats. Whole-genome sequences of two affected Abyssinians and 195 controls of other breeds (part of the 99 Lives initiative) were screened to prioritize potential disease-associated variants. Proteome and miRNAome from formalin-fixed paraffin-embedded kidney specimens of fully necropsied Abyssinian cats, three affected and three non-amyloidosis-affected were characterized. While the trigger of the disorder remains unclear, overall, (i) 35,960 genomic variants were detected; (ii) 215 and 56 proteins were identified as exclusive or overexpressed in the affected and control kidneys, respectively; (iii) 60 miRNAs were differentially expressed, 20 of which are newly described. With omics data integration, the general conclusions are: (i) the familial amyloid renal form in Abyssinians is not a simple monogenic trait; (ii) amyloid deposition is not triggered by mutated amyloidogenic proteins but is a mix of proteins codified by wild-type genes; (iii) the form is biochemically classifiable as AA amyloidosis.

Cryo-EM structure ofex vivofibrils associated with extreme AA amyloidosis prevalence in a cat shelter

“…Due to the conserved amyloidogenic nature of A-SAA, domestic animals develop systemic amyloidosis similarly to humans 2,33,34 . Among cats, Siamese and Abyssinian breeds were reported as particularly prone to amyloidosis due to a familial predisposition [35][36][37][38][39][40] . Strikingly, the close-to-extinct captive cheetah, from whose lineage DSH cat ancestors split about six million years ago, suffers from an extreme disease prevalence of 70%, likely facilitated by prion-like disease transmission [41][42][43][44] .…”

Renal amyloid‐A amyloidosis in cats: Characterization of proteinuria and biomarker discovery, and associations with kidney histology

“…44 The bond between SAA and apolipoproteins occurs through the SAA N-terminal fragment and prevents SAA misfolding because the unbound SAA is labile and prone to conformational change. [45][46][47] Of note, apolipoproteins have been observed in kidneys from humans, cats, and island foxes with renal AA amyloidosis, including apolipoproteins A-I, A-IV, and E. 26,27,48 Thus, they also might play an important role in shelter cats with the disease.…”

“…In the last decade, proteomics‐based technologies have played a pivotal role in the characterization of amyloid structure and related proteins in humans and animals 23‐25 . In 2 recent studies, apolipoprotein (Apo) E, Apo A‐I, and Apo I‐V were identified in renal samples from Abyssinian, Siamese and DSH cats with AA amyloidosis 26,27 . To the best of our knowledge, proteomics analysis of urine samples in cats with AA amyloidosis has not been carried out.…”

AA-amyloidosis in cats (Felis catus) housed in shelters

“…However, several hypotheses have been proposed, such as increased circulating concentrations of SAA along with defects in the degrading properties of monocytes or genetic structural abnormalities of proteins [3]. Many conditions, including neoplastic, inflammatory, and metabolic diseases are associated with high production of SAA in cats [9] but amyloidosis has been only sporadically reported in not predisposed breeds [10][11][12][13]; recently, the differences in SAA genetic sequences proved to not contribute to the pathogenesis of feline AA-amyloidosis both in Japanese domestic cats [14] and in Abyssinian breed [15]. Other factors, such as amyloidenhancing factors and glycosaminoglycans, may possibly take part in amyloidogenesis by accelerating amyloid-fibril deposition [16].…”