Case report: ocular manifestations of a gain-of-function mutation in CLCN6, a newly diagnosed disease

ABSTRACT

Background

In 2020, a new disease was reported by Polovitskaya et al., caused by a monoallelic, gain-of-function mutation in CLCN6, encoding the ClC-6 Cl−/H±exchanger.

Methods

Here, we report the ophthalmic findings of one of the first three patients with this disease (the proband) and review the findings in the other two patients in the literature.

Results

The CLCN6 gene is part of the voltage-dependent chloride channel protein family. It functions as either a chloride channel aiding in cell-volume regulation and acidification of intracellular organelles or as an antiporter, which are membrane proteins involved in the transport of molecules across a phospholipid membrane. This particular gene is found in late endosomes. Ion transport across endosome membranes is essential for endosomal function. The proband carried a de novo c.1658A>G (p.Tyr553Cys) mutation in CLCN6. The patient reported herein has a notable optic nerve appearance. The nerve initially appeared elevated. Over time, the optic nerve elevation appearance decreased, associated with progressive vision loss with a visual acuity of 20/470 at last follow-up.

Conclusion

While Clcn6−/− mice have been found to have a mild neuronal lysosomal storage phenotype, the three reported children with a de novo c.1658A>G (p.Tyr553Cys) variant displayed significant developmental delay and neurodegeneration.

KEYWORDS:

• CLCN6
• proband
• endosome

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Additional information

Funding

Research reported in this manuscript was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under Award Number(s) U01HG010215. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.This research is funded by an unrestricted grant from Research to Prevent Blindness.