Biallelic loss-of-function variants in RAX2, encoding a homeobox-containing Rax transcription factor, cause autosomal recessive inherited retinal disease

RAX2 encodes a member of the homeobox-containing Rax family of transcription factors, which play a pivotal role in late retinogenesis in vertebrate species by regulating the spatial expression of photoreceptor-specific genes. So far, only four monoallelic RAX2 variants have been tentatively implicated in autosomal dominant cone-dominated retinal disease. Here we report biallelic missense, frameshift and structural variants in RAX2 identified by whole exome sequencing, in five unrelated index cases of Belgian, British, Italian and Spanish origin, diagnosed with non-syndromic autosomal recessive retinitis pigmentosa (RP) with a variable age of onset. Protein structure analysis of the two novel missense variants revealed a loss of Rax2 protein folding and/or stability, in agreement with a loss-of-function effect. Modeling of the previously reported dominant RAX2 missense variant on the other hand demonstrated potential roles in homeodomain/DNA higher order complex formation with no effect on protein stability or DNA binding, thus compatible with a gain-of-function effect. Haplotype analysis in three Belgian RP cases sharing the same RAX2 frameshift variant c.335dup suggested a common ancestry. Fine-mapping and bio-informatics analysis of the two identified structural variants affecting RAX2 disentangled their underlying mechanisms. In summary, our findings support a role for RAX2 as a novel disease gene for autosomal recessive RP. This study uncovered the first structural variants affecting RAX2 and a founder allele in Belgian RP patients. The identification of biallelic pathogenic RAX2 variants in five unrelated families may suggest a role in other autosomal recessive RP cases with an unknown molecular diagnosis.

Publication year:2018