Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2019

Species-specific symbol: pd

Inheritance: Parshall et al. (1991): "Pedigree analysis and test-mating studies conclusively establish that inheritance is autosomal recessive."

Murgiano et al. (2019): "Pedigree analysis suggested monogenic autosomal recessive inheritance".

Mapping: Murgiano et al. (2019): "GWAS and homozygosity mapping defined a critical interval in the first 4,796,806 bp of CFA15."

Molecular basis: Zhang et al. (1998) showed that some Miniature Schnauzers with this disorder are homozygous for a missense mutation in codon 82 (CGA -> GGA) of the gene for phosducin, creating an amino acid substiturion of Arg -> Gly. However, since some affected dogs are heterozygous for this mutation, and other affecteds are homozygous for the normal allele, it remains an open question as to whether this mutation has anything to do with the disorder.

Zhang et al. (1999) "conclusively excluded four photoreceptor-specific genes [RHO, PRPH, GNAT1, ROM1] as candidates for pd by linkage analysis"

Murgiano et al. (2019) reported unpublished information from Aguirre, confirming that the phosducin variant reported by Zhang et al. (1998) "subsequently was found to not be disease-associated".

Murgiano et al. (2019) reported a likely causal variant as "a complex structural variant consisting of the duplication of exon 5 of the PPT1 gene along with a conversion and insertion (named PPT1^dci ). PPT1^dci was confirmed homozygous in a cohort of 22 cases, and 12 more cases were homozygous for the CFA15 haplotype. Additionally, the variant was found homozygous in 6 non-affected dogs of age higher than the average age of onset. . . . We detected the wildtype and three aberrant PPT1 transcripts in isolated white blood cell mRNA extracted from a PRA case homozygous for PPT1dci, and the aberrant transcripts involved inclusion of the duplicated exon 5 and novel exons following the activation of cryptic splice sites. No neurological signs were detected among the dogs homozygous for the PPT1^dci variant. Therefore, we propose PPT1^dci as causative for a non-syndromic form of PRA (PRA^PPT1 ) that shows incomplete penetrance in Miniature Schnauzers, potentially related to the presence of the wild-type transcript."

Breed: Miniature Schnauzer.

Associated gene: