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Glomerulopathy and mutations in NPHS1 and KIRREL2 in soft-coated Wheaten Terrier dogs

Abstract

Dogs of the soft-coated wheaten terrier breed (SCWT) are predisposed to adult-onset, genetically complex, protein-losing nephropathy (average onset age = 6.3 ± 2.0 years). A genome-wide association study using 62 dogs revealed a chromosomal region containing three statistically significant SNPs (p raw ≤ 4.13 × 10−8; p genome ≤ 0.005) when comparing DNA samples from affected and geriatric (≥14 years) unaffected SCWTs. Sequencing of candidate genes in the region revealed single nucleotide changes in each of two closely linked genes, NPHS1 and KIRREL2, which encode the slit diaphragm proteins nephrin and Neph3/filtrin, respectively. In humans, mutations in nephrin and decreased expression of Neph3 are associated with podocytopathy and protein-losing nephropathy. The base substitutions change a glycine to arginine in the fibronectin type 3 domain of nephrin and a proline to arginine in a conserved proline-rich region in Neph3. These novel mutations are not described in other species, nor were they found in 550 dogs of 105 other breeds, except in 3 dogs, including an affected Airedale terrier, homozygous for both substitutions. Risk for nephropathy is highest in dogs homozygous for the mutations (OR = 9.06; 95 % CI = 4.24–19.35). This is the first molecular characterization of an inherited podocytopathy in dogs and may serve as a model for continued studies of complex genetic and environmental interactions in glomerular disease.

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Acknowledgments

The authors thank Rachel Cianciolo, Donna Dambach, Mattie Hendrick, Rebecca Kessler, George Lees, Junlong Liu, Alisa Newton, Shelly Vaden, Brian Wilcock, and the many veterinarians, students, breeders, and SCWT owners who helped with this work. We received financial support from the Soft Coated Wheaten Terrier Club of America Endowment, Inc., and American Kennel Club – Canine Health Foundation.

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Correspondence to Meryl P. Littman.

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335_2012_9445_MOESM1_ESM.rtf

Genes located in the PLN-associated interval. The region between the three most significant SNPs is shown in light gray, with the flanking regions encompassing all SNPs with p < 6.7 × 10−7 (RTF 137 kb)

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Littman, M.P., Wiley, C.A., Raducha, M.G. et al. Glomerulopathy and mutations in NPHS1 and KIRREL2 in soft-coated Wheaten Terrier dogs. Mamm Genome 24, 119–126 (2013). https://doi.org/10.1007/s00335-012-9445-8

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Keywords

  • Focal Segmental Glomerulosclerosis
  • Alport Syndrome
  • Glomerular Filtration Barrier
  • NPHS1 Gene
  • Protein Nephrin