Abnormal Splicing in the Final Intron of PRX Results in Dominant Congenital Cataract Without Neurological Phenotype.

Purpose: Disrupted lens development can result in congenital cataract. Despite identifying over 50 genes linked to non-syndromic pediatric cataract, a causative mutation is found in only about 50% of affected families. Methods: Exome and/or genome sequencing was undertaken in families with unexplained congenital cataract. Results: Sequencing revealed heterozygous variants affecting splicing of the final intron of PRX in seven individuals from four families. PRX encodes periaxin, a protein necessary for the maintenance of peripheral nerve myelin and the proper organization of the lens cortex adherens junction. PRX has two major isoforms, differing in their final exon(s). For PRXb (L-PRX, 1461 amino acids), a small intron 6 separates exons 6 and 7; in PRXa (S-PRX, 147 amino acids), the intron is retained, generating a larger exon 6a but introducing an earlier stop codon. Loss-of-function variants affecting L-PRX (or both isoforms) cause recessive neurological phenotypes without cataract. The dominant cataract alleles identified here occur within the splice region of intron 6 and are predicted to cause abnormal splicing of PRXb (L-PRX). RNA sequencing confirmed aberrant splicing for all identified variants, including retention of intron 6, which ultimately results in a switch to the S-PRX isoform, and/or utilization of alternate donor or acceptor sites yielding small in-frame deletions in L-PRX. Conclusions: Splicing defects leading to the replacement of L-PRX by S-PRX and/or the presence of an aberrant L-PRX exert a significant negative effect on lens development, possibly through a gain-of-function or dominant-negative mechanism distinct from the one implicated in recessive neurological phenotypes.