{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n KLHL7 is a member of the BTB‐Kelch protein family that functions as a substrate adaptor in Cullin3‐based Cullin–RING E3 ubiquitin ligase complexes. Structural studies have revealed that, like other BTB–Kelch proteins, KLHL7 contains BTB and BACK domains that are critical for binding to Cul3 and for substrate recruitment, thereby facilitating the addition of Lys‐48–linked polyubiquitin chains and promoting proteasomal degradation of specific target proteins."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In the retina, mutations in KLHL7—most notably within its conserved BACK domain—impair its interaction with Cul3 and diminish E3 ligase activity. This dominant negative effect is associated with autosomal dominant retinitis pigmentosa, suggesting that failure to ubiquitinate and degrade key proteins in photoreceptor cells underlies the disease pathology."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, KLHL7 has been implicated in regulating nucleolar integrity through the ubiquitination of terminal uridylyl transferase 1 (TUT1). Expression of wild‐type KLHL7 promotes TUT1 ubiquitination and alters its nucleolar localization, whereas disease‐causing KLHL7 mutants do not elicit this effect, linking its E3 ligase function to maintenance of nucleolar homeostasis and, possibly, retinal cell viability."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its role in retinal degeneration, mutations in KLHL7 have been associated with a multisystem disorder resembling Crisponi syndrome/cold‐induced sweating syndrome. In these cases, recessive KLHL7 mutations contribute to a broader phenotype that includes neurodevelopmental delay and retinitis pigmentosa, highlighting the importance of KLHL7 in neuronal as well as retinal homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Autoantibodies to KLHL7 have also been detected in certain patients with paraneoplastic neurological syndromes. In these individuals, the nuclear expression of KLHL7 in neurons may trigger an immune response, suggesting an additional role in neural function and maintenance that, when dysregulated, could contribute to paraneoplastic processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, elevated KLHL7 expression has been linked with aggressive features in breast cancer, indicating that abnormal regulation of ubiquitin-mediated proteolysis via KLHL7 might contribute to oncogenic processes in tissues beyond the nervous system."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these studies underscore the critical role of KLHL7 in maintaining protein homeostasis through its function in targeted ubiquitination. Disruption of this role—either by loss-of-function mutations or aberrant expression—appears to contribute to a spectrum of pathologies, ranging from retinal degeneration and multisystem developmental syndromes to tumor progression and paraneoplastic neurological disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Peter Canning, Christopher D O Cooper, Tobias Krojer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M112.437996"}], "href": "https://doi.org/10.1074/jbc.M112.437996"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23349464"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23349464"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "James S Friedman, Joseph W Ray, Naushin Waseem, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2009.05.007"}], "href": "https://doi.org/10.1016/j.ajhg.2009.05.007"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19520207"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19520207"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yu Kigoshi, Fuminori Tsuruta, Tomoki Chiba "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquitin ligase activity of Cul3-KLHL7 protein is attenuated by autosomal dominant retinitis pigmentosa causative mutation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M111.245126"}], "href": "https://doi.org/10.1074/jbc.M111.245126"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21828050"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21828050"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Jaehyun Kim, Fuminori Tsuruta, Tomomi Okajima, et al. "}, {"type": "b", "children": [{"type": "t", "text": "KLHL7 promotes TUT1 ubiquitination associated with nucleolar integrity: Implications for retinitis pigmentosa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2017.10.049"}], "href": "https://doi.org/10.1016/j.bbrc.2017.10.049"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29032201"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29032201"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Andrea Angius, Paolo Uva, Insa Buers, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2016.05.026"}], "href": "https://doi.org/10.1016/j.ajhg.2016.05.026"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27392078"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27392078"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Lauren Jeffries, Jordan E Olivieri, Weizhen Ji, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Two siblings with a novel nonsense variant provide further delineation of the spectrum of recessive KLHL7 diseases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Med Genet (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejmg.2018.10.003"}], "href": "https://doi.org/10.1016/j.ejmg.2018.10.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30300710"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30300710"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "G Bredholt, A Storstein, M Haugen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Detection of autoantibodies to the BTB-kelch protein KLHL7 in cancer sera."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Scand J Immunol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1365-3083.2006.01821.x"}], "href": "https://doi.org/10.1111/j.1365-3083.2006.01821.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16918702"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16918702"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Sasagu Kurozumi, Chitra Joseph, Sultan Sonbul, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Clinical and biological roles of Kelch-like family member 7 in breast cancer: a marker of poor prognosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Breast Cancer Res Treat (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s10549-018-4777-z"}], "href": "https://doi.org/10.1007/s10549-018-4777-z"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29633055"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29633055"}]}]}]}