Fam8a1, an orphan gene, was captured by a retrovirus during primate evolution [4]. It is expressed ubiquitously with a testis-specific transcript in spermatogenesis [4]. Functionally, Fam8a1 is involved in the endoplasmic reticulum-associated degradation (ERAD) pathway. It engages with the HAF-H domain in the cytoplasmic domain of Hrd1, a central ubiquitin ligase in ERAD, and enhances the binding of Herp to Hrd1, which is essential for ERAD [1]. The ERAD pathway is crucial for maintaining cell homeostasis by eliminating misfolded proteins [1,5].

In Russian Blue cats, a 23-bp deletion in exon 1 of Fam8a1, introducing a frameshift and premature stop codon, is associated with REM sleep behavior disorder, urinary retention, and mydriasis. This variant is predicted to affect the assembly and activity of the ERAD pathway [3]. In human studies, Fam8a1 was among the genes whose expression was differentially regulated in various conditions. In SLE patients, its expression was found to be different compared to healthy controls, along with other genes like TRIM5 [2]. In obese subjects with type 2 diabetes, the expression of Fam8a1 was strongly correlated with changes in body weight, fasting plasma glucose, and glycosylated hemoglobin content after bariatric surgery [6]. In urothelial carcinomas, amplification of the 6p22 segment containing Fam8a1 was associated with increased gene expression [7].

In summary, Fam8a1 is significantly involved in the ERAD pathway maintaining cell homeostasis. Its abnormal expression or genetic variants are associated with various diseases, including sleep and neurological disorders in cats, and potentially autoimmune and metabolic diseases in humans. These findings from different models contribute to understanding the role of Fam8a1 in disease-related biological processes.

References:

1. Schulz, Jasmin, Avci, Dönem, Queisser, Markus A, Hoppe, Thorsten, Christianson, John C. 2017. Conserved cytoplasmic domains promote Hrd1 ubiquitin ligase complex formation for ER-associated degradation (ERAD). In Journal of cell science, 130, 3322-3335. doi:10.1242/jcs.206847. https://pubmed.ncbi.nlm.nih.gov/28827405/

2. Pan, Zhaobing, Yang, Qiaoshan, Zhang, Xiaojing, Zhou, Fusheng, Wen, Leilei. 2023. TRIM5 Promotes Systemic Lupus Erythematosus Through CD4(+) T Cells and Macrophage. In International journal of general medicine, 16, 3567-3580. doi:10.2147/IJGM.S416493. https://pubmed.ncbi.nlm.nih.gov/37614552/

3. Stee, Kimberley, Van Poucke, Mario, Huguet, Jaume Alomar, Peelman, Luc, Cornelis, Ine. . A FAM8A1 frameshift variant is associated with REM sleep behavior disorder, urinary retention, and mydriasis in Russian Blue cats. In Animal genetics, 56, e70013. doi:10.1111/age.70013. https://pubmed.ncbi.nlm.nih.gov/40266280/

4. Jamain, S, Girondot, M, Leroy, P, Fellous, M, Bourgeron, T. . Transduction of the human gene FAM8A1 by endogenous retrovirus during primate evolution. In Genomics, 78, 38-45. doi:. https://pubmed.ncbi.nlm.nih.gov/11707071/

5. Erzurumlu, Yalcin, Catakli, Deniz, Dogan, Hatice Kubra. 2023. Circadian Oscillation Pattern of Endoplasmic Reticulum Quality Control (ERQC) Components in Human Embryonic Kidney HEK293 Cells. In Journal of circadian rhythms, 21, 1. doi:10.5334/jcr.219. https://pubmed.ncbi.nlm.nih.gov/37033333/

6. Berisha, Stela Z, Serre, David, Schauer, Philip, Kashyap, Sangeeta R, Smith, Jonathan D. 2011. Changes in whole blood gene expression in obese subjects with type 2 diabetes following bariatric surgery: a pilot study. In PloS one, 6, e16729. doi:10.1371/journal.pone.0016729. https://pubmed.ncbi.nlm.nih.gov/21423737/

7. Heidenblad, Markus, Lindgren, David, Jonson, Tord, Månsson, Wiking, Höglund, Mattias. 2008. Tiling resolution array CGH and high density expression profiling of urothelial carcinomas delineate genomic amplicons and candidate target genes specific for advanced tumors. In BMC medical genomics, 1, 3. doi:10.1186/1755-8794-1-3. https://pubmed.ncbi.nlm.nih.gov/18237450/