Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease

Melissa Lee, Briana Vecchio-Pagán, Neeraj Sharma, Abdul Waheed, Xiaopeng Li, Karen S. Raraigh, Sarah Robbins, Sangwoo T. Han, Arianna L. Franca, Matthew J. Pellicore, Taylor A. Evans, Kristin Arcara, Hien Nguyen, Shan Luan, Deborah A Belchis, Jozef Hertecant, Joseph Zabner, William S. Sly, Garry R Cutting

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numberddw065
Pages (from-to)1923-1933
Number of pages11
JournalHuman Molecular Genetics
Volume25
Issue number10
DOIs
StatePublished - May 15 2016

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Sweat
Lung Diseases
Chlorides
Failure to Thrive
Sweat Glands
Hyponatremia
Pedigree
Epithelial Cells
Exome
Genetic Databases
Proteins
Madin Darby Canine Kidney Cells
Ion Transport
Cystic Fibrosis
Epithelium
carbonic anhydrase XII
RNA
Phenotype
Lung
Mutation

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease. / Lee, Melissa; Vecchio-Pagán, Briana; Sharma, Neeraj; Waheed, Abdul; Li, Xiaopeng; Raraigh, Karen S.; Robbins, Sarah; Han, Sangwoo T.; Franca, Arianna L.; Pellicore, Matthew J.; Evans, Taylor A.; Arcara, Kristin; Nguyen, Hien; Luan, Shan; Belchis, Deborah A; Hertecant, Jozef; Zabner, Joseph; Sly, William S.; Cutting, Garry R.

In: Human Molecular Genetics, Vol. 25, No. 10, ddw065, 15.05.2016, p. 1923-1933.

Research output: Contribution to journalArticle

Lee, M, Vecchio-Pagán, B, Sharma, N, Waheed, A, Li, X, Raraigh, KS, Robbins, S, Han, ST, Franca, AL, Pellicore, MJ, Evans, TA, Arcara, K, Nguyen, H, Luan, S, Belchis, DA, Hertecant, J, Zabner, J, Sly, WS & Cutting, GR 2016, 'Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease', Human Molecular Genetics, vol. 25, no. 10, ddw065, pp. 1923-1933. https://doi.org/10.1093/hmg/ddw065
Lee, Melissa ; Vecchio-Pagán, Briana ; Sharma, Neeraj ; Waheed, Abdul ; Li, Xiaopeng ; Raraigh, Karen S. ; Robbins, Sarah ; Han, Sangwoo T. ; Franca, Arianna L. ; Pellicore, Matthew J. ; Evans, Taylor A. ; Arcara, Kristin ; Nguyen, Hien ; Luan, Shan ; Belchis, Deborah A ; Hertecant, Jozef ; Zabner, Joseph ; Sly, William S. ; Cutting, Garry R. / Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 10. pp. 1923-1933.
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