Delineating the Molecular and Phenotypic Spectrum of the CNGA3-Related Cone Photoreceptor Disorder in Pakistani Families | [Abstract Book on Global Science Technology and Management Conference • 2023]

Author(s):

1. Sairah Yousaf: Department of Otorhinolaryngology, Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA

2. Nabeela Tariq: Department of Zoology, Sardar Bahadur Khan Women’s University, Quetta, Pakistan

3. Zureesha Sajid: Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan

4. Shakeel A. Sheikh: Molecular Biology and Genetics Department, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan

5. Tasleem Kausar: Department of Zoology, Government Sadiq College Women University, Bahawalpur, Pakistan

6. Yar M. Waryah: Scientific Ophthalmic and Research Laboratory, Sindh Institute of Ophthalmology and Visual Sciences, Hyderabad, Pakistan

7. Rehan S. Shaikh: Institute of Molecular Biology and Biotechnology, Bahauddin Zakariya University, Multan, Pakistan; Center for Applied Molecular Biology, University of the Punjab, Lahore, Pakistan

8. Ali M. Waryah: Molecular Biology and Genetics Department, Liaquat University of Medical and Health Sciences, Jamshoro, Pakistan

9. Saumil Sethna: Department of Otorhinolaryngology, Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA

10. Saima Riazuddin: Department of Otorhinolaryngology, Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA

11. Zubair M. Ahmed: Department of Otorhinolaryngology, Head & Neck Surgery, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, MD 21201, USA; Department of Ophthalmology and Visual Sciences, School of Medicine, University of Maryland, Baltimore, MD 21201, USA

Abstract:

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. Families’ enrolment and clinical examination yielded the data of families affected with cone dystrophies. The enrollment and examination followed the tenets of the Declaration Helsinki. Two families (PKAB149, PKED06) were enrolled from the Punjab province of Pakistan, while the third family (LUSG06) was identified from the Sindh province. Informed written consent was obtained from all participants. Sanger sequencing of all the coding exons and exon-intron junctions of CNGA3 was performed using the proband DNA samples from families PKAB149 and PKED06. While whole exome sequencing (WES) was used to identify the disease-associated variants in family LUSG06. NCBI conserved domain was used to generate CNGA3 protein structural domains, while Clustal omega multiple alignment was used to assess the conservation of the identified variants across several different species. Varsome (www.varsome.com, accessed on 15 October 2021) was used for pathogenicity predictions, and allele frequencies were obtained from gnomAD (https://gnomad.broadinstitute.org/, accessed on 15 October 2021) database. The 3-Dimensional (3D) protein structures were generated using Phyre2 server (http://www.sbg.bio.ic.ac.uk /phyre2/html/page. cgi? id=index, accessed on 15 October 2021) with “Intensive Mode” option, which is a combination of template-based modeling and ab initio methods. In order to determine the impact of the newly identified mutation on CNG channel functionality, homomeric as well as heteromeric CNG channels were heterologously expressed and surface expression quantified in human embryonic kidney 293 (HEK293) cells. 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>G, p.(Asn276Ser); c.847C>T, p.(Arg283Trp); c.1279C>T, p.(Arg427Cys)) in CNGA3, the a-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.

Page(s): 119-119

DOI: DOI not available

Published: Journal: Abstract Book on Global Science Technology and Management Conference, Volume: 0, Issue: 0, Year: 2023

Keywords:

CNGA3 , Cone photoreceptor dysfunction , Phenotypic Spectrum

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