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Pathogenicity and Function Analysis of Two Novel SLC4A11 Variants in Patients With Congenital Hereditary Endothelial

Tianjiao Zhen1, Ya Li2, Qingge Guo2

  • 1Henan University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, China.

Translational Vision Science & Technology
|October 3, 2023
PubMed

Insights

This study identified two novel SLC4A11 variants in a congenital hereditary endothelial dystrophy (CHED) family. The K263R variant caused mitochondrial dysfunction, but an antioxidant, SkQ1, showed protective effects, suggesting a potential new therapy for CHED.

Area of Science:

  • Genetics
  • Ophthalmology
  • Cell Biology

Background:

  • Congenital hereditary endothelial dystrophy (CHED) is an inherited eye condition.
  • The SLC4A11 gene plays a crucial role in corneal endothelial function.
  • Novel variants in SLC4A11 can lead to CHED, but their exact mechanisms are not fully understood.

Purpose of the Study:

  • To investigate the pathogenicity and function of two new SLC4A11 variants in CHED.
  • To analyze the in vitro function of the SLC4A11 (K263R) mutant.
  • To explore potential therapeutic interventions for CHED.

Main Methods:

  • Ophthalmic examination of a CHED patient.
  • Whole-exome and Sanger sequencing for mutation identification.
  • In vitro studies using HEK293T cells transfected with wild-type and mutant SLC4A11, treated with SkQ1.
  • Measurement of cellular respiration, reactive oxygen species (ROS), mitochondrial membrane potential, and apoptosis.

Main Results:

  • Two novel heterozygous SLC4A11 variants were identified in the CHED family.
  • The c.1464-1G>T variant was confirmed as pathogenic.
  • The c.788A>G (p.Lys263Arg) variant led to increased ROS and apoptosis, decreased mitochondrial membrane potential and oxygen consumption in vitro.
  • SkQ1 treatment mitigated these negative effects.

Conclusions:

  • Two novel pathogenic SLC4A11 variants were identified in a CHED family.
  • The SLC4A11 (K263R) variant induces mitochondrial dysfunction and apoptosis.
  • The antioxidant SkQ1 demonstrates a protective effect, indicating its potential as a novel therapeutic agent for CHED.
Abstract

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