A Conformation-altering variant in TXNDC15 linked to Joubert syndrome

Abstract Ciliopathies are a group of genetic disorders resulting from defects in the primary cilia. Numerous mutations in cilia-associated proteins have been linked to these conditions. Here, we report a pediatric patient presenting clinical features consistent with Joubert Syndrome and genomic analyses revealing two compound heterozygous variants in the TXNDC15 gene: a missense variant p.(R235W) and a two-nucleotide deletion within the first intron region. The study also focuses on the structural consequences of the R235W replacement on the TXNDC15 protein. Structural modelling indicates that TXNDC15 has a Thioredoxin domain core, preceded by a long intrinsically disordered region (IDR1) and followed by a C-terminal transmembrane α-helix likely involved in membrane anchoring. The Thioredoxin domain connects to this helix via a second intrinsically disordered region (IDR2), interrupted by a short α-helix (residues 305–313). Notably, Asp309, the central residue of this helix salt bridges with Arg235 —substituted by tryptophan in the patient— at the Thioredoxin domain. Molecular dynamics simulations reveal that the R235W replacement prevents the residues 235–309 bridge and destabilizes the 305–313 α-helix within IDR2. This alteration likely perturbs the conformational landscape of IDR2. Given the patient’s phenotype, these findings allow to hypothesize that the disrupted bridge may compromise TXNDC15’s integrity to properly support ciliary function, thereby contributing to the development of the observed phenotype.