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Biallelic Variants in EPHA2 Identified in Three Large Inbred Families with Early-Onset Cataract

Hereditary congenital cataract (HCC) is clinically and genetically heterogeneous. We investigated HCC that segregates in three inbred families (LUCC03, LUCC16, and LUCC24). Ophthalmological examinations revealed cataracts with variability related to the age of onset segregating in a recessive manner...

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Autores principales: Jarwar, Priya, Sheikh, Shakeel Ahmed, Waryah, Yar Muhammad, Ujjan, Ikram Uddin, Riazuddin, Saima, Waryah, Ali Muhammad, Ahmed, Zubair M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508826/
https://www.ncbi.nlm.nih.gov/pubmed/34638995
http://dx.doi.org/10.3390/ijms221910655
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author Jarwar, Priya
Sheikh, Shakeel Ahmed
Waryah, Yar Muhammad
Ujjan, Ikram Uddin
Riazuddin, Saima
Waryah, Ali Muhammad
Ahmed, Zubair M.
author_facet Jarwar, Priya
Sheikh, Shakeel Ahmed
Waryah, Yar Muhammad
Ujjan, Ikram Uddin
Riazuddin, Saima
Waryah, Ali Muhammad
Ahmed, Zubair M.
author_sort Jarwar, Priya
collection PubMed
description Hereditary congenital cataract (HCC) is clinically and genetically heterogeneous. We investigated HCC that segregates in three inbred families (LUCC03, LUCC16, and LUCC24). Ophthalmological examinations revealed cataracts with variability related to the age of onset segregating in a recessive manner in these families. Exome sequencing of probands identified a novel homozygous c.2710delG;p.(Val904Cysfs*36) EPHA2 variant in LUCC03 and a known homozygous c.2353G>A;p.(Ala785Thr) EPHA2 variant in the other two recessive families. EPHA2 encodes a transmembrane tyrosine kinase receptor, which is primarily involved in membrane-transport, cell-cell adhesion, and repulsion signaling processes. Computational structural modeling predicts that substitution of a threonine for an alanine p.(Ala785Thr) results in the formation of three new hydrogen bonds with the neighboring residues, which causes misfolding of EPHA2 in both scenarios. Insights from our study will facilitate counseling regarding the molecular and phenotypic landscape of EPHA2-related HCC.
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spelling pubmed-85088262021-10-13 Biallelic Variants in EPHA2 Identified in Three Large Inbred Families with Early-Onset Cataract Jarwar, Priya Sheikh, Shakeel Ahmed Waryah, Yar Muhammad Ujjan, Ikram Uddin Riazuddin, Saima Waryah, Ali Muhammad Ahmed, Zubair M. Int J Mol Sci Brief Report Hereditary congenital cataract (HCC) is clinically and genetically heterogeneous. We investigated HCC that segregates in three inbred families (LUCC03, LUCC16, and LUCC24). Ophthalmological examinations revealed cataracts with variability related to the age of onset segregating in a recessive manner in these families. Exome sequencing of probands identified a novel homozygous c.2710delG;p.(Val904Cysfs*36) EPHA2 variant in LUCC03 and a known homozygous c.2353G>A;p.(Ala785Thr) EPHA2 variant in the other two recessive families. EPHA2 encodes a transmembrane tyrosine kinase receptor, which is primarily involved in membrane-transport, cell-cell adhesion, and repulsion signaling processes. Computational structural modeling predicts that substitution of a threonine for an alanine p.(Ala785Thr) results in the formation of three new hydrogen bonds with the neighboring residues, which causes misfolding of EPHA2 in both scenarios. Insights from our study will facilitate counseling regarding the molecular and phenotypic landscape of EPHA2-related HCC. MDPI 2021-09-30 /pmc/articles/PMC8508826/ /pubmed/34638995 http://dx.doi.org/10.3390/ijms221910655 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Brief Report
Jarwar, Priya
Sheikh, Shakeel Ahmed
Waryah, Yar Muhammad
Ujjan, Ikram Uddin
Riazuddin, Saima
Waryah, Ali Muhammad
Ahmed, Zubair M.
Biallelic Variants in EPHA2 Identified in Three Large Inbred Families with Early-Onset Cataract
title Biallelic Variants in EPHA2 Identified in Three Large Inbred Families with Early-Onset Cataract
title_full Biallelic Variants in EPHA2 Identified in Three Large Inbred Families with Early-Onset Cataract
title_fullStr Biallelic Variants in EPHA2 Identified in Three Large Inbred Families with Early-Onset Cataract
title_full_unstemmed Biallelic Variants in EPHA2 Identified in Three Large Inbred Families with Early-Onset Cataract
title_short Biallelic Variants in EPHA2 Identified in Three Large Inbred Families with Early-Onset Cataract
title_sort biallelic variants in epha2 identified in three large inbred families with early-onset cataract
topic Brief Report
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508826/
https://www.ncbi.nlm.nih.gov/pubmed/34638995
http://dx.doi.org/10.3390/ijms221910655
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