A novel SVA retrotransposon insertion in the CHM gene results in loss of REP-1 causing choroideremia

ABSTRACT

Background

Choroideremia is an X-linked retinal disease characterized by progressive atrophy of the choroid and retinal pigment epithelium caused by mutations in the CHM gene. SVA (SINE-R/VNTR/Alu) elements are a type of non-autonomous retrotransposon that occasionally self-replicate, reinsert randomly into a gene, and cause disease. Intragenic SVA insertions have been reported as the mechanism underlying a number of diseases including a syndromic form of retinal dystrophy, but have never been found in CHM.

Materials and Methods

Here we identified and characterized a novel hemizygous SVA insertion, c.97_98inSVA (p.Arg33insSVA), in exon 2 of CHM in a male choroideremia patient. The SVA insertion’s impact was evaluated by establishing a patient-derived lymphoblastoid cell line as a source of RNA for mRNA analysis of the CHM transcript, and protein for immunoblot analysis of Rab Escort Protein 1 (REP-1).

Results

Immunoblot analysis revealed the absence of REP-1 protein, while a smaller than expected PCR product was amplified from cDNA. Sequencing of this PCR product showed skipping of exon 2, denoted r.50_116del. Ophthalmic examination including psychophysical tests, visual electrophysiology, and fundus imaging showed the patient’s phenotype was consistent with severe early manifestations of choroideremia.

Conclusions

This case is the first report of a SVA insertion in the CHM gene causing choroideremia.

KEYWORDS:

• SVA insertion
• CHM
• REP-1
• choroideremia
• retrotransposon

Declaration of interest

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

Additional information

Funding

This work was supported by the National Institute of Health under grant number [EY09076], Foundation Fighting Blindness, Choroideremia Research Foundation Canada, Inc., Foundation Fighting Blindness Canada, Alberta Innovates Health Solutions, and Canadian Institutes of Health Research.