Categories: Vision / eye phene , Nervous system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 602679 (gene) , 618770 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2024

Species-specific name: Progressive retinal, central, and peripheral neurodegeneration

Species-specific symbol: PCYT2-D

Mapping: Assuming a monogenic autosomal recessive mode of inheritance, Christen et al. (2024) performed linkage analysis in a family consisting of the two parents and a litter of 8 puppies. Results were combined with homozygosity analysis in a total of eight affected dogs. The two approaches yielded "two genomic segments on chromosomes 3 and 9 showed simultaneous linkage in the family and homozygosity in the eight cases. Taken together, these two intervals spanned 15.2 Mb or 0.64% of the 2.4 Gb dog genome and were considered the critical interval for the subsequent analyses." (Christen et al., 2024)

Molecular basis: Christen et al. (2024) performed whole genome sequencing of an affected dog and searched for private homozygous variants against 1495 control genomes. The "analysis identified one single homozygous private protein-changing variant in a functional candidate gene within the critical interval. The variant, chr9:1,207,490A>G or XM_038546296.1:c.4A>G, was located in the PCYT2 gene and is predicted to result in an amino acid substitution in the encoded ethanolamine-phosphate cytidylyltransferase 2, XP_038402224.1:(p.Ile2Val). The other 15 private protein-changing variants within the critical interval were not located in genes known to cause similar combined ocular and neurologic phenotypes in humans, mice, or domestic animals." (Christen et al. 2024) Christen et al. (2024) genotyped a total of 1091 Saarlooswolfdogs for the PCYT2:A>G variant and found strong association to the phenotype. Eleven affected dogs were homozygous for the mutant G/G genotype. The authors identified another 3 homozygous mutant dogs in their cohort that were reported as clinically helathy by their owners. These dogs were all younger than the average age of diagnosis for the affected dogs. Ophthalmological examination of one of these three dogs revealed signs of beginning retinal degeneration and reduced rod-cone responses, which was consistent with an early stage of generalized progressive retinal atrophy (prcd-PRA). PCYT2 encodes phosphate cytidylyltransferase 2, an enzyme involved in lipid metabolism. More specifically, PCYT2 is required for the synthesis of phosphatidylethanolamines (PE), an important class of phospholipids in mammalian cell membranes. PE are particularly enriched in nervous tissues, such as the white matter of the brain or the retina, where they can account for up to 45% of all phospholipids. To obtain a functional confirmation of the hypothesized PCYT2 deficiency in homozygous mutant dogs, Christen et al. (2024) performed a lipidomics analysis on blood samples from dogs with the three different genotypes. "Homozygous mutant dogs showed strikingly altered lipid profiles compared to heterozygous or homozygous wildtype dogs. A significant accumulation of ether lipids, mainly of the PC-O/P class, but also of PE-O/P species, was detected in the six analyzed homozygous mutant dogs" (Christen et al., 2024).

Clinical features: "Clinical signs involved early adult onset retinal degeneration and adult-onset neurological deficits including gait abnormalities, hind limb weakness, tremors, ataxia, cognitive decline and behavioral changes such as aggression towards the owner." (Christen et al., 2024) The first noticable clinical signs in the affected dogs involved a progressive loss of vision. Affected dogs developed prcd-PRA that let to blindness in older dogs. In six affected dogs of the study, the PRA diagnosis was made between 20 and 46 months of age (av 36 m, SD: 17 m) (Christen et al., 2024). Subsequent to the visual decline "The eleven affected dogs additionally exhibited a range of neurological and neuromuscular signs, including gait abnormalities, hind limb weakness, tremors, ataxia, cognitive decline and behavioral changes such as aggression towards the owner. ... Additionally, epileptic seizures were reported in cases 5, 6, 8, and 11. MRI was reportedly done at four years of age in cases 7, 9 and 10. The MRIs of cases 7 and 10 showed brain atrophy compatible with neurodegenerative disease. Notably, MRI findings in case 9 were normal even though it was performed after the onset of neurological signs." (Christen et al. 2024)

Pathology: "Histopathology of case 9, euthanized at 63 months of age, revealed severe bilateral retinal degeneration with loss of layering and atrophy. The outer and inner nuclear layers were thin and partially fused, and the outer plexiform layer and the rod/cone layer were barely visible. The inner plexiform layer was loose, and the number of ganglion cells was severely reduced. Additionally, there was bilateral cataract with presence of capsular epithelium (posterior migration of lens epithelium) and Morgagnian globules at the caudal poles. Brain and spinal cord showed scattered hypertrophy and hyperplasia of white matter astrocytes, which had a large amount of cytoplasm and large irregular to lobulated nuclei. These changes were most prominent in the spinal cord, brainstem, cerebellar medulla and in the corona radiata. Multiple small glial nodules were present in the white matter of the spinal cord and brainstem. The cerebellar foliae appeared slightly thin with widening of the sulci. Gliosis was observed in the molecular layer, and Purkinje cells appeared to be irregularly distributed. The neuropil of the caudate nucleus, and to a lesser extent the cortex, contained well-defined vacuoles of variable sizes that were associated with astrocytic hypertrophy. In addition to the astrocytic hypertrophy, axonal swelling/degeneration and dilation of myelin sheaths containing axonal fragments were observed in the spinal cord. The changes were most severe in the dorsal funiculi, and particularly in the cervical spinal cord. However, milder changes were also found in other funiculi. The cuneate and gracile nucleus in the brainstem contained multiple axonal spheroids. Myelin ballooning was observed multifocally in the dorsal root ganglia, with multiple axons being swollen, pale, and surrounded by a very thin myelin sheet. Multifocal mild meningothelial proliferation was additionally observed in the subarachnoid space of spinal cord and cerebellum. Skeletal muscles multifocally contained single myofibers or myofiber groups that were atrophic and triangular to flat in appearance, with multifocal internalization of nuclei. Multiple terminal nerve fibers showed increased interstitial fibrosis that separated the axons." (Christen et al., 2024)

Prevalence: At the time of publication, the carrier frequency in the population was 19.1% in a cohort of 998 dogs (Christen et al., 2024).

Breed: Saarloos Wolfhond (Dog) (VBO_0201158).
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: