Identification and characterization of a novel mutation in the carbonic anhydrase IV gene that causes retinitis pigmentosa

Bernardo V. Alvarez, Eranga N. Vithana, Zhenglin Yang, Adrian H. Koh, Kit Yeung, Victor Yong, Haley J. Shandro, Yali Chen, Prasanna Kolatkar, Paaventhan Palasingam, Kang Zhang, Tin Aung, Joseph R. Casey

Research output: Contribution to journalArticle

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Abstract

PURPOSE. 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 ≤1% of Chinese patients with RP.

Original languageEnglish
Pages (from-to)3459-3468
Number of pages10
JournalInvestigative Ophthalmology and Visual Science
Volume48
Issue number8
DOIs
Publication statusPublished - 1 Aug 2007
Externally publishedYes

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Carbonic Anhydrase IV
Retinitis Pigmentosa
Mutation
Genes
Bicarbonates
Retina
Exons
Sodium-Bicarbonate Symporters
Retinal Diseases
Glycosylphosphatidylinositols
Chromosomes, Human, Pair 17
HEK293 Cells
Missense Mutation
Zinc
Homeostasis
Complementary DNA
Chromosomes
Acids
Membranes

ASJC Scopus subject areas

  • Ophthalmology

Cite this

Identification and characterization of a novel mutation in the carbonic anhydrase IV gene that causes retinitis pigmentosa. / Alvarez, Bernardo V.; Vithana, Eranga N.; Yang, Zhenglin; Koh, Adrian H.; Yeung, Kit; Yong, Victor; Shandro, Haley J.; Chen, Yali; Kolatkar, Prasanna; Palasingam, Paaventhan; Zhang, Kang; Aung, Tin; Casey, Joseph R.

In: Investigative Ophthalmology and Visual Science, Vol. 48, No. 8, 01.08.2007, p. 3459-3468.

Research output: Contribution to journalArticle

Alvarez, BV, Vithana, EN, Yang, Z, Koh, AH, Yeung, K, Yong, V, Shandro, HJ, Chen, Y, Kolatkar, P, Palasingam, P, Zhang, K, Aung, T & Casey, JR 2007, 'Identification and characterization of a novel mutation in the carbonic anhydrase IV gene that causes retinitis pigmentosa', Investigative Ophthalmology and Visual Science, vol. 48, no. 8, pp. 3459-3468. https://doi.org/10.1167/iovs.06-1515
Alvarez, Bernardo V. ; Vithana, Eranga N. ; Yang, Zhenglin ; Koh, Adrian H. ; Yeung, Kit ; Yong, Victor ; Shandro, Haley J. ; Chen, Yali ; Kolatkar, Prasanna ; Palasingam, Paaventhan ; Zhang, Kang ; Aung, Tin ; Casey, Joseph R. / Identification and characterization of a novel mutation in the carbonic anhydrase IV gene that causes retinitis pigmentosa. In: Investigative Ophthalmology and Visual Science. 2007 ; Vol. 48, No. 8. pp. 3459-3468.
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T1 - Identification and characterization of a novel mutation in the carbonic anhydrase IV gene that causes retinitis pigmentosa

AU - Alvarez, Bernardo V.

AU - Vithana, Eranga N.

AU - Yang, Zhenglin

AU - Koh, Adrian H.

AU - Yeung, Kit

AU - Yong, Victor

AU - Shandro, Haley J.

AU - Chen, Yali

AU - Kolatkar, Prasanna

AU - Palasingam, Paaventhan

AU - Zhang, Kang

AU - Aung, Tin

AU - Casey, Joseph R.

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N2 - PURPOSE. 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 ≤1% of Chinese patients with RP.

AB - PURPOSE. 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 ≤1% of Chinese patients with RP.

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