Categories: Vision / eye phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 606068 (trait) , 613596 (gene)

Links to relevant human diseases in MONDO:

• MONDO:0011630: retinitis pigmentosa 28

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: yes

Key variant known: yes

Year key variant first reported: 2014

Cross-species summary: Renamed from "Retinal atrophy, progressive, type 3, FAM161A-related" to "Retinal atrophy, progressive, FAM161A-related" [01/082024]

Species-specific name: Progressive retinal atrophy 3, PRA3 (Tibetan Terrier); Progressive retinal atrophy 6, PRA6 (English Shepherd)

Inheritance: Bjerkas and Narfstrom (1994) reported data supporting autosomal recessive inheritance.

Mapping: From a GWAS conducted on 22 affected and 10 control Tibetan Spaniels, each genotyped with an Illumina SNP20 BeadChip (yielding 15,674 informative SNPs), Downs and Mellersch (2014) mapped this disorder to a 3.8Mb candidate region on chromosome CFA10.

Molecular basis: Encouraged by the fact that a comparative (human) candidate gene (namely FAM161A, mutations in which cause retinosis pigmentosa (RP) 28) shows conserved synteny with the candidate region identified in their GWAS (see Mapping section), Downs and Mellersch (2014) next-gen sequenced the 3.8Mb candidate region in 4 affected, 2 obligate carriers and 2 unaffecteds, identifying the most likely candidate causal variant as a large insertion in the region of exon 5 of FAM161A. Subsequent Sanger-sequencing of this region in 29 affecteds, 10 obligate carriers and 41 unaffecteds identified a ~230bp insertion containing a 132bp short interspersed nuclear element (SINE), near the splice acceptor site of exon 5. As reported by Downs and Mellersch (2014), "Analysis of mRNA from an affected dog revealed that the SINE causes exon skipping, resulting in a frame shift, leading to a downstream premature termination codon and possibly a truncated protein product."
Stanbury et al. (2024) investigated English Shepherds which "were diagnosed with PRA at approximately 5 years old and tested clear of all published PRA genetic variants. ... [The authors] utilised a combined approach of whole genome sequencing of the probands and homozygosity mapping of four cases and 22 controls and identified a short interspersed nuclear element within an alternatively spliced exon in FAM161A. The XP_005626197.1 c.17929_ins210 variant was homozygous in six PRA cases and heterozygous or absent in control dogs, consistent with a recessive mode of inheritance. The insertion is predicted to extend exon 4 by 39 aberrant amino acids followed by an early termination stop codon."

Prevalence: While the FAM161A insertion reporteed by Downs and Mellersch (2014) has strong claims to being causative (see Molecular section), the authors cautioned that heterogeneity exists: "This [FAM161A, omia.variant:925] mutation segregates with the disease in 22 out of 35 cases tested (63%). Of the PRA controls, none are homozygous for the mutation, 15% carry the mutation and 85% are homozygous wildtype. This mutation was also identified in Tibetan Terriers, although our results indicate that PRA is genetically heterogeneous in both Tibetan Spaniels and Tibetan Terriers."

Breeds: English Shepherd (Dog) (VBO_0200496), Tibetan Spaniel (Dog) (VBO_0201352), Tibetan Terrier (Dog) (VBO_0201353).
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: