title: Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease.
abstract: Elevated sweat chloride levels, failure to thrive (FTT), and lung disease are characteristic features of cystic fibrosis (CF, OMIM #219700). Here we describe variants in CA12 encoding carbonic anhydrase XII in two pedigrees exhibiting CF-like phenotypes. Exome sequencing of a white American adult diagnosed with CF due to elevated sweat chloride, recurrent hyponatremia, infantile FTT and lung disease identified deleterious variants in each CA12 gene: c.908-1 G>A in a splice acceptor and a novel frameshift insertion c.859_860insACCT. In an unrelated consanguineous Omani family, two children with elevated sweat chloride, infantile FTT, and recurrent hyponatremia were homozygous for a novel missense variant (p.His121Gln). Deleterious CFTR variants were absent in both pedigrees. CA XII protein was localized apically in human bronchiolar epithelia and basolaterally in the reabsorptive duct of human sweat glands. Respiratory epithelial cell RNA from the adult proband revealed only aberrant CA12 transcripts and in vitro analysis showed greatly reduced CA XII protein. Studies of ion transport across respiratory epithelial cells in vivo and in culture revealed intact CFTR-mediated chloride transport in the adult proband. CA XII protein bearing either p.His121Gln or a previously identified p.Glu143Lys missense variant localized to the basolateral membranes of polarized Madin-Darby canine kidney (MDCK) cells, but enzyme activity was severely diminished when assayed at physiologic concentrations of extracellular chloride. Our findings indicate that loss of CA XII function should be considered in individuals without CFTR mutations who exhibit CF-like features in the sweat gland and lung.
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Melissa
authors.initials: M
authors.lastname: Lee
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Briana
authors.initials: B
authors.lastname: Vecchio-Pagán
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Edward A. Doisy Department of Biochemistry, St. Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Abdul
authors.initials: A
authors.lastname: Waheed
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Xiaopeng
authors.initials: X
authors.lastname: Li
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Karen S
authors.initials: KS
authors.lastname: Raraigh
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Robbins
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Sangwoo T
authors.initials: ST
authors.lastname: Han
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Arianna L
authors.initials: AL
authors.lastname: Franca
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Pellicore
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Taylor A
authors.initials: TA
authors.lastname: Evans
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Arcara
authors.affiliation: Edward A. Doisy Department of Biochemistry, St. Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Hien
authors.initials: H
authors.lastname: Nguyen
authors.affiliation: Edward A. Doisy Department of Biochemistry, St. Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Luan
authors.affiliation: Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA and.
authors.forename: Deborah
authors.initials: D
authors.lastname: Belchis
authors.affiliation: Tawam Hospital, United Arab Emirates University, Al Ain, UAE.
authors.forename: Jozef
authors.initials: J
authors.lastname: Hertecant
authors.affiliation: Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Zabner
authors.affiliation: Edward A. Doisy Department of Biochemistry, St. Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Sly
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA, gcutting@jhmi.edu.
authors.forename: Garry R
authors.initials: GR
authors.lastname: Cutting
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D002256:Carbonic Anhydrases / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D004285:Dogs; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006720:Homozygote; D006801:Humans; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008171:Lung Diseases / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013542:Sweat / Q000378:metabolism*
chemical_list: D002712:Chlorides; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D002256:Carbonic Anhydrases; C477378:carbonic anhydrase XII