{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T04:48:18Z","timestamp":1777438098069,"version":"3.51.4"},"reference-count":30,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T00:00:00Z","timestamp":1648512000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000055","name":"National Institute on Deafness and Other Communication Disorders","doi-asserted-by":"publisher","award":["R01DC016295"],"award-info":[{"award-number":["R01DC016295"]}],"id":[{"id":"10.13039\/100000055","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Cone photoreceptor dysfunction represents a clinically heterogenous group of disorders characterized by nystagmus, photophobia, reduced central or color vision, and macular dystrophy. Here, we described the molecular findings and clinical manifestations of achromatopsia, a partial or total absence of color vision, co-segregating with three known missense variants of CNGA3 in three large consanguineous Pakistani families. Fundus examination and optical coherence tomography (OCT) imaging revealed myopia, thin retina, retinal pigment epithelial cells loss at fovea\/perifovea, and macular atrophy. Combination of Sanger and whole exome sequencing revealed three known homozygous missense variants (c.827A&gt;G, p.(Asn276Ser); c.847C&gt;T, p.(Arg283Trp); c.1279C&gt;T, p.(Arg427Cys)) in CNGA3, the \u03b1-subunit of the cyclic nucleotide-gated cation channel in cone photoreceptor cells. All three variants are predicted to replace evolutionary conserved amino acids, and to be pathogenic by specific in silico programs, consistent with the observed altered membrane targeting of CNGA3 in heterologous cells. Insights from our study will facilitate counseling regarding the molecular and phenotypic landscape of CNGA3-related cone dystrophies.<\/jats:p>","DOI":"10.3390\/genes13040617","type":"journal-article","created":{"date-parts":[[2022,3,29]],"date-time":"2022-03-29T21:44:52Z","timestamp":1648590292000},"page":"617","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Delineating the Molecular and Phenotypic Spectrum of the CNGA3-Related Cone Photoreceptor Disorder in Pakistani Families"],"prefix":"10.3390","volume":"13","author":[{"given":"Sairah","family":"Yousaf","sequence":"first","affiliation":[{"name":"Department of Otorhinolaryngology\u2014Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nabeela","family":"Tariq","sequence":"additional","affiliation":[{"name":"Department of Zoology, Sardar Bahadur Khan Women\u2019s University, Quetta 81800, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2337-5441","authenticated-orcid":false,"given":"Zureesha","family":"Sajid","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan 60000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shakeel A.","family":"Sheikh","sequence":"additional","affiliation":[{"name":"Molecular Biology and Genetics Department, Liaquat University of Medical and Health Sciences, Jamshoro 76090, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tasleem","family":"Kausar","sequence":"additional","affiliation":[{"name":"Department of Zoology, Government Sadiq College Women University, Bahawalpur 63100, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yar M.","family":"Waryah","sequence":"additional","affiliation":[{"name":"Scientific Ophthalmic and Research Laboratory, Sindh Institute of Ophthalmology and Visual Sciences, Hyderabad 71000, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rehan S.","family":"Shaikh","sequence":"additional","affiliation":[{"name":"Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan 60000, Pakistan"},{"name":"Center for Applied Molecular Biology, University of the Punjab, Lahore 54500, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2596-9032","authenticated-orcid":false,"given":"Ali M.","family":"Waryah","sequence":"additional","affiliation":[{"name":"Molecular Biology and Genetics Department, Liaquat University of Medical and Health Sciences, Jamshoro 76090, Pakistan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saumil","family":"Sethna","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\u2014Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saima","family":"Riazuddin","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\u2014Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"},{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2914-4502","authenticated-orcid":false,"given":"Zubair M.","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Department of Otorhinolaryngology\u2014Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"},{"name":"Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"},{"name":"Department of Ophthalmology and Visual Sciences, School of Medicine, University of Maryland, Baltimore, MD 21201, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/978-3-540-68964-5_7","article-title":"Cyclic nucleotide-gated channels","volume":"191","author":"Biel","year":"2009","journal-title":"Handb. Exp. Pharmacol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Michalakis, S., Becirovic, E., and Biel, M. (2018). Retinal Cyclic Nucleotide-Gated Channels: From Pathophysiology to Therapy. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19030749"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"8721","DOI":"10.1074\/jbc.M115.696138","article-title":"The B3 Subunit of the Cone Cyclic Nucleotide-gated Channel Regulates the Light Responses of Cones and Contributes to the Channel Structural Flexibility","volume":"291","author":"Ding","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/ncomms1466","article-title":"Molecular mechanism for 3:1 subunit stoichiometry of rod cyclic nucleotide-gated ion channels","volume":"2","author":"Shuart","year":"2011","journal-title":"Nat. Commun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1152\/physrev.00008.2002","article-title":"Cyclic nucleotide-gated ion channels","volume":"82","author":"Kaupp","year":"2002","journal-title":"Physiol Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e24550","DOI":"10.7554\/eLife.24550","article-title":"The Na+\/Ca2+, K+ exchanger NCKX4 is required for efficient cone-mediated vision","volume":"6","author":"Vinberg","year":"2017","journal-title":"Elife"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.1016\/j.bbrc.2004.07.122","article-title":"Guanylate cyclase-activating proteins: Structure, function, and diversity","volume":"322","author":"Palczewski","year":"2004","journal-title":"Biochem Biophys Res. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1167\/iovs.16-20427","article-title":"The Clinical Phenotype of CNGA3-Related Achromatopsia: Pretreatment Characterization in Preparation of a Gene Replacement Therapy Trial","volume":"58","author":"Zobor","year":"2017","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1001\/jamaophthalmol.2014.1032","article-title":"Identification of CNGA3 mutations in 46 families: Common cause of achromatopsia and cone-rod dystrophies in Chinese patients","volume":"132","author":"Li","year":"2014","journal-title":"JAMA Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1136\/bjophthalmol-2014-305432","article-title":"Novel CNGA3 mutations in Chinese patients with achromatopsia","volume":"99","author":"Liang","year":"2015","journal-title":"Br. J. Ophthalmol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1016\/j.ajhg.2016.12.003","article-title":"Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease","volume":"100","author":"Carss","year":"2017","journal-title":"Am. J. Hum. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1007\/s00439-006-0314-y","article-title":"Achromatopsia: The CNGB3 p.T383fsX mutation results from a founder effect and is responsible for the visual phenotype in the original report of uniparental disomy 14","volume":"121","author":"Wiszniewski","year":"2007","journal-title":"Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3389\/fphys.2015.00177","article-title":"Inherited macular degeneration-associated mutations in CNGB3 increase the ligand sensitivity and spontaneous open probability of cone cyclic nucleotide-gated channels","volume":"6","author":"Meighan","year":"2015","journal-title":"Front. Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping using next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1038\/mp.2016.109","article-title":"Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability","volume":"22","author":"Riazuddin","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/ejhg.2014.136","article-title":"Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy","volume":"23","author":"Shaikh","year":"2015","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1007\/s10384-011-0070-y","article-title":"Genetic analysis of four Pakistani families with achromatopsia and a novel S4 motif mutation of CNGA3","volume":"55","author":"Saqib","year":"2011","journal-title":"Jpn. J. Ophthalmol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/935","article-title":"Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel","volume":"19","author":"Kohl","year":"1998","journal-title":"Nat. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"722","DOI":"10.1086\/323613","article-title":"CNGA3 mutations in hereditary cone photoreceptor disorders","volume":"69","author":"Wissinger","year":"2001","journal-title":"Am. J. Hum. Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1111\/j.1460-9568.2008.06195.x","article-title":"Functional analysis of human CNGA3 mutations associated with colour blindness suggests impaired surface expression of channel mutants A3(R427C) and A3(R563C)","volume":"27","author":"Koeppen","year":"2008","journal-title":"Eur. J. Neurosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1016\/j.proghi.2009.03.001","article-title":"Recent advances in quantitative colocalization analysis: Focus on neuroscience","volume":"44","author":"Zinchuk","year":"2009","journal-title":"Prog. Histochem. Cytochem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1211","DOI":"10.1016\/j.ajo.2013.06.033","article-title":"Diagnostic fundus autofluorescence patterns in achromatopsia","volume":"156","author":"Fahim","year":"2013","journal-title":"Am. J. Ophthalmol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/bs.pmbts.2018.10.002","article-title":"Diseases associated with mutations in CNGA3: Genotype-phenotype correlation and diagnostic guideline","volume":"161","author":"Sun","year":"2019","journal-title":"Prog Mol. Biol. Transl. Sci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3864","DOI":"10.1167\/iovs.06-1521","article-title":"CNGB3 achromatopsia with progressive loss of residual cone function and impaired rod-mediated function","volume":"48","author":"Khan","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1080\/13816810.2017.1368087","article-title":"CNGB3 mutations cause severe rod dysfunction","volume":"39","author":"Maguire","year":"2018","journal-title":"Ophthalmic Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1124\/molpharm.120.000180","article-title":"Identification of Chemical and Pharmacological Chaperones for Correction of Trafficking-Deficient Mutant Cyclic Nucleotide-Gated A3 Channels","volume":"99","author":"Tager","year":"2021","journal-title":"Mol. Pharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1167\/iovs.11-8168","article-title":"CNGA3 deficiency affects cone synaptic terminal structure and function and leads to secondary rod dysfunction and degeneration","volume":"53","author":"Xu","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Dai, X., He, Y., Zhang, H., Zhang, Y., Liu, Y., Wang, M., Chen, H., and Pang, J.J. (2017). Long-term retinal cone rescue using a capsid mutant AAV8 vector in a mouse model of CNGA3-achromatopsia. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188032"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Reichel, F.F., Michalakis, S., Wilhelm, B., Zobor, D., Muehlfriedel, R., Kohl, S., Weisschuh, N., Sothilingam, V., Kuehlewein, L., and Kahle, N. (2021). Three-year results of phase I retinal gene therapy trial for CNGA3-mutated achromatopsia: Results of a non randomised controlled trial. Br. J. Ophthalmol.","DOI":"10.1136\/bjophthalmol-2021-319067"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/4\/617\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:46:09Z","timestamp":1760136369000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/13\/4\/617"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,3,29]]},"references-count":30,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2022,4]]}},"alternative-id":["genes13040617"],"URL":"https:\/\/doi.org\/10.3390\/genes13040617","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,3,29]]}}}