Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 22, Issue 19, Pages -Publisher
MDPI
DOI: 10.3390/ijms221910655
Keywords
cataract; EPHA2; hereditary congenital cataract; exome sequencing; inbred population; tyrosine kinase receptor; Eph receptor
Funding
- National Institutes of Health (NIH)-National Institute on Deafness and Other Communication Disorders (NIDCD) [R01DC016295]
- Higher Education Commission of Pakistan, NRPU [8128]
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Hereditary congenital cataract (HCC) is clinically and genetically heterogeneous, with cataracts segregating in a recessive manner in three families with variability related to age of onset. Exome sequencing identified a novel EPHA2 variant in LUCC03 and a known variant in the other families. Computational modeling predicted that the variants cause misfolding of EPHA2. This study provides insights into the molecular and phenotypic landscape of EPHA2-related HCC.
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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