Categories: Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 600722 (gene) , 256730 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2019

Cross-species summary: Renamed from ;Photoreceptor dysplasia' to 'Photoreceptor dysplasia, PPT1-related' [09/06/2024]

Species-specific name: Progressive retinal atrophy, type 1

Species-specific symbol: pd; PRA^PPT1

History: The molecular genetics of this trait was independently studied by two laboratories. Murgiano et al. (2019) reported a complex structural variant in PPT1 as most likely causal variant, whereas Kaukonen et al. (2020) suggested causality for a non-coding putative silencer variant in HIVEP3. After the two conflicting publications appeared, the principal investigators of both studies discussed their findings and agreed on a consensus interpretation compatible with all experimental observations, which was published in a formal commentary (Aguirre et al. 2020). When all data are considered, the PPT1 structural variant is the most likely causal variant, but very difficult to genotype. The HIVEP3 SNV, while most likely not the causal variant, is strongly associated with the phenotype and may represent a useful marker as it can be robustly genotyped (Aguirre et al. 2020).

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."

Markers: An intronic SNV in HIVEP3 is strongly associated with the disease and can be used as a marker (Kaukonen et al. 2020; Aguirre et al. 2020). The most likely causal structural variant in PPT1 is very difficult to genotype and so far could only be reliably genotyped from whole genome sequence data (Aguirre et al. 2020).

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, some affected dogs are heterozygous for this mutation, and other affecteds are homozygous for the normal allele. 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 (2019) reported unpublished information from Aguirre, confirming that the phosducin variant reported by Zhang et al.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". 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 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." The authors noted that other variants in the PPT1 gene cause a more severe phenotype: 'OMIA 001504-9615 : Neuronal ceroid lipofuscinosis, 1', and outline likely reasons why for the PPT1^dci variant, clinical signs are restricted to loss of vision. Kaukonen et al. (2020) investigated Miniature Schnauzers with clinical signs of PRA and recognized two clinically distinct subtypes, termed type 1 (this entry) and type 2 (see OMIA 002253-9615). The authors then identified an intronic SNV in HIVEP3 as potentially causal variant. In light of the findings by Murgiano et al. (2019), the evidence for the causality of the HIVEP3 variant is insufficient. The lead authors of both studies published a consensus commentary: "Thus, the genetic evidence is unable to distinguish between the HIVEP3 and PPT1 variants as potential causes of PRA. ... functional considerations favor causality of the coding PPT1 structural variant over the intronic HIVEP3 SNV" (Aguirre et al. 2020).

Clinical features: Murgiano et al. (2019) reported "Based on the limited number of cases examined by one of the authors (GDA), PRA-affected dogs were clinically indistinguishable from the earlier described photoreceptor dysplasia cases (Parshall et al. 1991). Clinical examinations using biomicroscopy and indirect ophthalmoscopy showed that affected dogs were normal when examined at 10 months of age or earlier. Subsequently, fundus changes indicative of PRA developed. By 3 years of age, affected dogs showed advanced retinal disease. They had slow and incomplete pupillary light reflexes, and showed poor vision in familiar surroundings or preferred to be in a crate and not moving around. ... Fundus abnormalities at ∼3 years of age were characteristic of mid-stage disease (Parshall et al. 1991), consisted of marked attenuation or loss of retinal vessels, diffuse hyperreflectivity and ridging of the tapetal region (an indication of retinal thinning) and RPE loss and pigment migration in the non-tapetal regions of the eye. Cataracts were not present at this time. Progression to end-stage retinal atrophy and blindness occurred with age, although we could not specify the age when these changes occurred as most of the samples and clinical records were submitted from dogs prior to this advanced disease stage." 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). All 12 cases examined in Kaukonen et al. (2020) were totally blind before the age of five.

Pathology: Kaukonen et al. (2020): "OCT [Optical Coherence Tomography] imaging . . . showed complete loss of the photoreceptor layer "

Breed: Miniature Schnauzer (Dog) (VBO_0200896).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: