Abstract
Purpose :
Axial Spondylometaphyseal dysplasia (axial SMD) with cone-rod dystrophy caused by mutations in CFAP410 is a very rare syndrome. The mechanisms by which the mutations caused the disease remained largely unknown. We explored the pathogenicity and performed functional analysis of two compound heterozygous CFAP410 mutations identified in an axial SMD with cone-rod dystrophy patient.
Methods :
A 4-year-old boy complained decreased vision underwent ocular examinations together with systemic X-ray check. Blood sample was taken for WES gene sequencing. Pathogenicity of identified mutations was determined by ACMG guideline. Mutated plasmids were constructed and transferred to HEK293T cells. Cell cycle, protein stability and degradation, and protein ubiquitination level was measured.
Results :
The best-corrected visual acuity was 0.25 bilaterally. Fundus showed uneven granular pigment disorder in the periphery of the retina. SS-OCT showed thinning and atrophy of the outer retina, residual ellipsoid bands in the fovea and macular staphyloma. Scotopic and photopic ERG responses severe reduced. The patient was short and X-ray showed mild scoliosis. Two heterozygous missense mutations, c.319T >C (p.Tyr107His) and c.347C>T (p.Pro116Leu) in exon 4 of the CFAP410, were pathogenic by the ACMG guideline. In vitro, mutations affected a highly conserved residue could affect cell cycle. Immunofluorescence and Western blotting showed that the mutant proteins decreased protein stability but increase protein degradation. Meanwhile, CO-IP data suggested that ubiquitination level was altered in the mutated plasmids transferred cells.
Conclusions :
Compound heterozygous CFAP410 mutations c.319T >C and c.347C>T in CFAP410 caused axial SMD with cone-rod dystrophy. The pathogenic mechanisms may be associated with alternations of protein stability and degradation through the ubiquitin-proteasome pathway.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.