Possibly relevant human trait(s) and/or gene(s) (MIM number): 606649 (gene)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2020

History: Kaukonen et al. (2020) described two types of PRA in the Miniature Schnauzer breed, the first characterised by "severe PRA findings including total blindness before the age of five years" and named type 1 (this entry), and the second characterised by "milder symptoms, slower progression with some visual capacity left at the time of examination and an average age of onset seven years" (named type 2; see OMIA 002253-9615).

Inheritance: Kaukonen et al. (2020) reported that type 1 PRA in Miniature Schnauzers exhibited autosomal recessive inheritance.

Mapping: A GWAS involving 10 type-1 cases and 33 controls, each genotyped with the the Illumina CanineHD BeadChip (yielding 100,501 informative SNPs), followed by homozygosity analysis, enabled Kaukonen et al. (2020) to map this disorder to a "7.2 Mb [that] spans from 213,416 bp to 7,403,217 bp" on chromosome CFA15.

Molecular basis: Whole-genome sequencing of two type-1 cases and one control, and subsequent filtering, enabled Kaukonen et al. (2020) to identify "an intronic SNV (g.1,432,293G>A) in the transcription factor encoding the ortholog of human immunodeficiency virus type I enhancer binding protein 3 gene (HIVEP3" as the likely causal variant, which "segregated completely with the disease and the association with the type 1 phenotype was more than 10 billion times stronger than any other variants in the region (p = 4.0x10-25)". The authors reported that the variant "lies within a regulatory site with the predicted binding site of HAND1::TCF3 transcription factor complex. Luciferase assays suggested that mutated regulatory sequence increases expression. Case-control retinal expression comparison of six best HAND1::TCF3 target genes were analyzed with quantitative reverse-transcriptase PCR assay and indicated overexpression of EDN2 and COL9A2 in the affected retina. Defects in both EDN2 and COL9A2 have been previously associated with retinal degeneration."

Clinical features: Kaukonen et al. (2020) reported that the clinical signs and age of onset "closely resemble" those reported in the same breed by Jeong et al. (2013)

Pathology: Kaukonen et al. (2020): "OCT imaging . . . showed complete loss of the photoreceptor layer "

Prevalence: Kaukonen et al. (2020) reported that among the 514 Miniature Schnauzer samples in their dog DNA bank, "456 (88.7%) were wild-type, 55 (10.7%) heterozygous and three (0.58%) homozygous for the variant. The identified three homozygotes were the PRA cases in the breed screening cohort and were clinically identical to type 1 cases. . . . The variant was not found from 735 genomes of different breeds available through The Dog Biomedical Variant Database Consortium dataset, which agrees with our hypothesis of a recent variant."

Breed: Miniature Schnauzer.

Associated gene: