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Preliminary studies in heterologous expression systems demonstrate that the mutation leads to a nonfunctional transporter, which is expressed and trafficked to the plasma membrane alongside wild-type NKCC1. The truncated protein, visible at higher molecular sizes, indicates either enhanced dimerization or misfolded aggregate. No significant dominant-negative effect was observed. K<jats:sup>+<\/jats:sup> transport experiments performed in fibroblasts from the patient showed reduced total and NKCC1-mediated K<jats:sup>+<\/jats:sup> influx. The absence of a bumetanide effect on K<jats:sup>+<\/jats:sup> influx in patient fibroblasts only under hypertonic conditions suggests a deficit in NKCC1 regulation. We propose that disruption in NKCC1 function might affect sensory afferents and\/or smooth muscle cells, as their functions depend on NKCC1 creating a Cl<jats:sup>\u2212<\/jats:sup> gradient across the plasma membrane. This Cl<jats:sup>\u2212<\/jats:sup> gradient allows the \u03b3-aminobutyric acid (GABA) receptor or other Cl<jats:sup>\u2212<\/jats:sup> channels to depolarize the membrane affecting processes such as neurotransmission or cell contraction. Under this hypothesis, disrupted sensory and smooth muscle function in a diverse set of tissues could explain the patient's phenotype.<\/jats:p>","DOI":"10.1101\/mcs.a001289","type":"journal-article","created":{"date-parts":[[2018,9,14]],"date-time":"2018-09-14T16:30:35Z","timestamp":1536942635000},"page":"a001289","source":"Crossref","is-referenced-by-count":54,"title":["A patient with multisystem dysfunction carries a truncation mutation in human <i>SLC12A2<\/i>, the gene encoding the Na-K-2Cl cotransporter, NKCC1"],"prefix":"10.1101","volume":"2","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3702-1599","authenticated-orcid":false,"given":"Eric","family":"Delpire","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynne","family":"Wolfe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bianca","family":"Flores","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rainelli","family":"Koumangoye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cara C.","family":"Schornak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salma","family":"Omer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Pusey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Markello","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Adams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"246","published-online":{"date-parts":[[2016,11,14]]},"reference":[{"key":"2021112406062173000_2.6.a001289.1","doi-asserted-by":"crossref","first-page":"C579","DOI":"10.1152\/ajpcell.2001.281.2.C579","article-title":"Contractile regulation of the Na+-K+-2Cl\u2212 cotransporter in vascular smooth muscle","volume":"281","year":"2001","journal-title":"Am J Physiol Cell Physiol"},{"key":"2021112406062173000_2.6.a001289.2","doi-asserted-by":"crossref","unstructured":"Alvarez-Leefmans FJ . 2009. 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