title: A patient with multisystem dysfunction carries a truncation mutation in humanSLC12A2, the gene encoding the Na-K-2Cl cotransporter, NKCC1.
abstract: This study describes a 13-yr-old girl with orthostatic intolerance, respiratory weakness, multiple endocrine abnormalities, pancreatic insufficiency, and multiorgan failure involving the gut and bladder. Exome sequencing revealed a de novo, loss-of-function allele inSLC12A2, the gene encoding the Na-K-2Cl cotransporter-1. The 11-bp deletion in exon 22 results in frameshift (p.Val1026Phefs*2) and truncation of the carboxy-terminal tail of the cotransporter. 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+transport experiments performed in fibroblasts from the patient showed reduced total and NKCC1-mediated K+influx. The absence of a bumetanide effect on K+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-gradient across the plasma membrane. This Cl-gradient allows the γ-aminobutyric acid (GABA) receptor or other Cl-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.
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Eric
authors.identifier: 0000-0002-3702-1599
authors.initials: E
authors.lastname: Delpire
authors.affiliation: Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Lynne
authors.initials: L
authors.lastname: Wolfe
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Bianca
authors.initials: B
authors.lastname: Flores
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Rainelli
authors.initials: R
authors.lastname: Koumangoye
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Cara C
authors.initials: CC
authors.lastname: Schornak
authors.affiliation: Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
authors.forename: Salma
authors.initials: S
authors.lastname: Omer
authors.affiliation: Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pusey
authors.affiliation: Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Lau
authors.affiliation: Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Markello
authors.affiliation: Undiagnosed Diseases Program, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Adams
mesh_terms: D000293:Adolescent; D000483:Alleles; D002352:Carrier Proteins / Q000235:genetics; D002462:Cell Membrane / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D009154:Mutation; D017384:Sequence Deletion / Q000235:genetics; D012964:Sodium / Q000378:metabolism; D012982:Sodium, Dietary / Q000378:metabolism; D028021:Sodium-Potassium-Chloride Symporters / Q000235:genetics; D064506:Solute Carrier Family 12, Member 2 / Q000235:genetics* / Q000378:metabolism; D000073359:Exome Sequencing / Q000379:methods
chemical_list: D002352:Carrier Proteins; D002712:Chlorides; C578877:SLC12A2 protein, human; D012982:Sodium, Dietary; D028021:Sodium-Potassium-Chloride Symporters; D064506:Solute Carrier Family 12, Member 2; D012964:Sodium
keywords: autonomic bladder dysfunction; chronic pain; orthostatic hypotension; small intestinal dysmotility