{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent studies have revealed that WASHC4—also known as SWIP or KIAA1033—is an indispensable subunit of the pentameric WASH complex, whose primary cellular role is to regulate endosomal protein sorting. WASHC4 participates in orchestrating the formation of localized F‐actin patches by stimulating Arp2/3-mediated actin polymerization, a process essential for the fission of transport tubules emerging from endosomes. In addition to its canonical role via retromer-dependent recruitment, WASHC4 directly anchors the complex to the endosomal membrane through a retromer-independent mechanism. This membrane targeting is mediated by its ability to bind specific phosphoinositide species, with phosphatidylinositol-3,5-bisphosphate (PI[3,5]P2) appearing to be critical for proper subcellular localization. Furthermore, interactions with endocytic adaptor proteins—illustrated by its association with partners of the clathrin machinery—support a role for WASHC4 in coupling endocytosis to membrane trafficking."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies have underscored the clinical significance of WASHC4 function in the nervous system. In a consanguineous family with autosomal recessive intellectual disability, a non‐synonymous mutation in the SWIP gene was shown to dramatically reduce protein levels and destabilize the entire WASH complex—suggesting that proper complex assembly is crucial for normal cellular activity in the brain."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Similarly, exome sequencing in additional patients with syndromic intellectual disability revealed compound heterozygous variants in KIAA1033/WASHC4 that were associated with a heterogeneous phenotype including learning difficulties, cranial size abnormalities, skeletal anomalies, and focal brain malformations."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Complementarily, a mouse model carrying the analogous SWIPP1019R mutation recapitulated endo-lysosomal disruptions and exhibited both cognitive and motor deficits, reinforcing the notion that impairment of WASHC4 function—and thus of endosomal trafficking—can drive neurodegenerative features."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "You Fu Pan, Ing-Marie Viklund, Heng Hang Tsai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The ulcerative colitis marker protein WAFL interacts with accessory proteins in endocytosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biol Sci (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7150/ijbs.6.163"}], "href": "https://doi.org/10.7150/ijbs.6.163"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20376207"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20376207"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Vojtěch Dostál, Tereza Humhalová, Pavla Beránková, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Identification of a novel candidate gene for non-syndromic autosomal recessive intellectual disability: the WASH complex member SWIP."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mol Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1093/hmg/ddr158"}], "href": "https://doi.org/10.1093/hmg/ddr158"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21498477"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21498477"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Mirna Assoum, Ange-Line Bruel, Melissa L Crenshaw, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Novel KIAA1033/WASHC4 mutations in three patients with syndromic intellectual disability and a review of the literature."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.61487"}], "href": "https://doi.org/10.1002/ajmg.a.61487"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31953988"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31953988"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jamie L Courtland, Tyler Wa Bradshaw, Greg Waitt, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Genetic disruption of WASHC4 drives endo-lysosomal dysfunction and cognitive-movement impairments in mice and humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.61590"}], "href": "https://doi.org/10.7554/eLife.61590"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33749590"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33749590"}]}]}]}