title: Identification and characterization of a novel mutation in the carbonic anhydrase IV gene that causes retinitis pigmentosa.
abstract: OBJECTIVE
  The autosomal dominant retinitis pigmentosa (adRP) gene on chromosome 17, region q22 (RP17), was recently identified as a glycosylphosphatidylinositol membrane-anchored zinc metalloenzyme (protein CAIV), highly expressed in the choriocapillaris of the eye and undetectable in the retina. Only two missense mutations have thus far been identified in the gene CA4. Functional analysis of these mutations demonstrated that retinal disease may result from perturbation of pH homeostasis in the outer retina, after disruption of CAIV and sodium bicarbonate cotransporter 1 (NBC1)-mediated bicarbonate transport. CA4 was screened in a panel of patients with RP, to expand the mutation spectrum of this novel adRP gene and understand its pathogenic mechanism.
  
  
  METHODS
  A total of 96 patients with simplex RP and adRP of Chinese ethnicity were screened for mutations in the eight coding exons of the CA4 gene by bidirectional sequencing. Functional consequences of CA4 mutations on the NBC1-mediated bicarbonate transport were studied by measuring bicarbonate fluxes in HEK293 cells cotransfected with NBC1 and CA4 mutant cDNAs.
  
  
  RESULTS
  Thirteen sequence alterations were identified, including a novel mutation within exon 3 of CA4 (R69H) in a patient with simplex RP. R69H was not found in 432 normal chromosomes. R69H CAIV impaired NBC1-mediated pH recovery after acid load.
  
  
  CONCLUSIONS
  A novel mutation has been identified in CA4 that provides further evidence that impaired pH regulation may underlie photoreceptor degeneration in RP17. This study indicates that, as with European patients with RP, mutations in CA4 also account for <or=1% of Chinese patients with RP.
authors.affiliation: Membrane Protein Research Group, Department of Physiology, University of Alberta, Edmonton Alberta, Canada.
authors.forename: Bernardo V
authors.initials: BV
authors.lastname: Alvarez
authors.forename: Eranga N
authors.initials: EN
authors.lastname: Vithana
authors.forename: Zhenglin
authors.initials: Z
authors.lastname: Yang
authors.forename: Adrian H
authors.initials: AH
authors.lastname: Koh
authors.forename: Kit
authors.initials: K
authors.lastname: Yeung
authors.forename: Victor
authors.initials: V
authors.lastname: Yong
authors.forename: Haley J
authors.initials: HJ
authors.lastname: Shandro
authors.forename: Yali
authors.initials: Y
authors.lastname: Chen
authors.forename: Prasanna
authors.initials: P
authors.lastname: Kolatkar
authors.forename: Paaventhan
authors.initials: P
authors.lastname: Palasingam
authors.forename: Kang
authors.initials: K
authors.lastname: Zhang
authors.forename: Tin
authors.initials: T
authors.lastname: Aung
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Casey
mesh_terms: D000595:Amino Acid Sequence; D044466:Asian People / Q000235:genetics*; D001639:Bicarbonates / Q000378:metabolism; D030741:Carbonic Anhydrase IV / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002886:Chromosomes, Human, Pair 17; D004252:DNA Mutational Analysis; D005110:Extracellular Space / Q000201:enzymology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D047468:Immunoprecipitation; D007668:Kidney / Q000166:cytology; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D017434:Protein Structure, Tertiary; D012174:Retinitis Pigmentosa / Q000208:ethnology* / Q000235:genetics* / Q000378:metabolism; D027982:Sodium-Bicarbonate Symporters / Q000378:metabolism
chemical_list: D001639:Bicarbonates; C498898:SLC4A4 protein, human; D027982:Sodium-Bicarbonate Symporters; D030741:Carbonic Anhydrase IV