Abstract
We assessed a large consanguineous Pakistani family (PKAB157) segregating early onset low vision problems. Funduscopic and electroretinographic evaluation of affected individuals revealed juvenile cone-rod dystrophy (CRD) with maculopathy. Other clinical symptoms included loss of color discrimination, photophobia and nystagmus. Whole-exome sequencing, segregation and haplotype analyses demonstrated that a transition variant (c.955T>C; p.(Cys319Arg)) in CNGA3 co-segregated with the CRD phenotype in family PKAB157. The ability of CNGA3 channel to influx calcium in response to agonist, when expressed either alone or together with the wild-type CNGB3 subunit in HEK293 cells, was completely abolished due to p.Cys319Arg variant. Western blotting and immunolocalization studies suggest that a decreased channel density in the HEK293 cell membrane due to impaired folding and/or trafficking of the CNGA3 protein is the main pathogenic effect of the p.Cys319Arg variant. Mutant alleles of the human cone photoreceptor cyclic nucleotide-gated channel (CNGA3) are frequently associated with achromatopsia. In rare cases, variants in CNGA3 are also associated with cone dystrophy, Leber’s congenital amaurosis and oligo cone trichromacy. The identification of predicted p.(Cys319Arg) missense variant in CNGA3 expands the repertoire of the known genetic causes of CRD and phenotypic spectrum of CNGA3 alleles.
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Acknowledgements
We thank the families for their participation and cooperation. We also thank Thomas Jaworek and Muhammad Asim Bhatti for technical assistance. The work in Pakistan was supported by a research grant (HEC-1262) to RSS from the Higher Education Commission of Islamabad. This work was supported through a grant from the German Ministry for Education and Research (BMBF; IonNeuroNet, FZ. 01GM1105A to BW) and the National Institutes of Health – National Institute on Deafness and Other Communication Disorders grant (R01DC012564 to ZMA). ZMA is also a recipient of an RPB Career Development Award.
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Shaikh, R., Reuter, P., Sisk, R. et al. Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy. Eur J Hum Genet 23, 473–480 (2015). https://doi.org/10.1038/ejhg.2014.136
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DOI: https://doi.org/10.1038/ejhg.2014.136
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