Prevalence of Variant Alleles Associated with Protein-Losing Nephropathy in Soft-Coated Wheaten Terriers
Meryl P. Littman; Michael G. Raducha; Paula S. Henthorn
School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
Variant alleles in NPHS1 and KIRREL2, the genes that encode the slit diaphragm proteins nephrin and filtrin/Neph3, respectively, were previously found associated with protein-losing nephropathy (PLN) in Soft-Coated Wheaten Terriers (SCWT) by a genome-wide association study and subsequent gene sequencing of candidate genes in a statistically significant interval that differed among dogs with PLN compared with geriatric (14–18 year old) SCWT. Genotyping assays were developed for both of the single nucleotide polymorphisms (SNPs) in these genes that are in linkage disequilibrium in the breed. Homozygous-positive dogs were shown to be at highest risk for the development of PLN; heterozygous dogs were at intermediate risk; and homozygous-negative dogs were at low risk for the development of PLN.1
A prevalence study was performed to ascertain if breeders could safely remove carrier dogs in one generation. Cheek swab, blood, or semen samples were tested from 1549 SCWT dogs of all ages (median 4 yrs). Haplotypes are described as 1-1 (homozygous negative), 1-2 (heterozygous), and 2-2 (homozygous positive) for the PLN-associated variant alleles. The following table shows the frequencies found in various countries.
| |
1-1
%
|
1-2
%
|
2-2
%
|
Variant allele
frequency (%)
|
|
USA, n = 1095**
(Hardy-Weinberg expected frequencies in the USA)
|
34
(33)
|
47
(49)
|
19
(18)
|
43
|
|
Canada, n = 155
Total USA and Canada, n = 1250**
|
42.5
35
|
44.5
47
|
13
18
|
35
42
|
|
Nordic countries, n = 125
|
42
|
44
|
14
|
36
|
|
UK/Ireland, n = 119
|
66
|
24
|
10
|
22
|
|
Other (Australia, Poland, Argentina), n = 55*
|
55.5
|
42
|
3.5
|
25
|
|
Total all countries, n = 1549 (unknown sex, n = 13)
- Females, n = 898**
- Males, n = 639
|
39
39
39
|
44
44
44
|
17
17
17
|
39
39
39
|
* Includes 1 Mi, undetermined NPHS1; 1-2 KIRREL2
** Includes 1 Fi, 1-2 NPHS1; 1-1 KIRREL2
Without genetic counseling with the knowledge of these haplotypes and assuming random breeding, the variant allele frequency would remain 43% in the USA. This high frequency indicates that it would be unwise to cull all carriers (1-2 or 2-2 dogs) of the variant alleles in one generation, thereby risking loss of genetic diversity, increased inbreeding, and the potential of increasing the incidence of other deleterious genetic traits. An approach to avoid producing high-risk homozygous-positive (2-2) dogs would be to preferably breed desirable heterozygous (1-2) or homozygous-positive (2-2) dogs to homozygous-negative (1-1) dogs.
Instructions for DNA submissions are available at www.scwtca.org/health/dnatest.htm.
References
1. Littman MP, Wiley CA, Raducha MG, Henthorn PS. Glomerulopathy and mutations in NPHS1 and KIRREL2 in soft-coated Wheaten terrier dogs. Mamm Genome. 2013;24:119–126.