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Eur J Hum Genet. 2015 Apr;23(4):473-80. doi: 10.1038/ejhg.2014.136. Epub 2014 Jul 23.

Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy.

Author information

1
Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan.
2
Molecular Genetics Laboratory, Institute for Ophthalmic Research, University Clinics Tuebingen, Tuebingen, Germany.
3
Division of Pediatric Ophthalmology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
4
Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.
5
Institute of Ophthalmology, Mayo Hospital, King Edward Medical University, Lahore, Pakistan.
6
1] Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan [2] Department of Otorhinolaryngology Head and Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD, USA.

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.

PMID:
25052312
PMCID:
PMC4666578
DOI:
10.1038/ejhg.2014.136
[Indexed for MEDLINE]
Free PMC Article

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