Mode of inheritance:Autosomal recessive
Mutational spectrum
Frameshift / nonsense / multiexon deletions
Canonical splice-site mutations:
Missense variants: affecting conserved residues in the tubby domain (e.g. p.Cys204Trp, p.Arg408His).
Predicted effect:Loss of function or severely hypomorphic alleles
No homozygotes seen in population databases (gnomAD) → consistent with rarity and pathogenicity.
Pathophysiologic Mechanism
TULP3is an adaptor for the IFT-A complex, required for trafficking of multiple integral membrane proteins to the primary cilium.
Mutant TULP3 → loss of ciliary localization of:
GPR161 (negative regulator of Sonic Hedgehog signalling)
ARL13Band INPP5E (important for phosphoinositide balance in cilia)
Consequence: defective ciliary composition and signalling leading to abnormal profibrotic pathway activation.
Dysregulated signaling pathways
Transcriptomic (RNA-seq) studies in patient fibroblasts:
Upregulation of TGF-βand WNT/β-catenin signalling genes
Downregulation of TGF-β inhibitor SMAD7
Activation of cardiomyopathy-associated gene clusters which is consistent with chronic activation of profibrotic cascades.
DNA-damage response defects
TULP3 shown to interact with SIRT1, a nuclear deacetylase that regulates TP53 and fibrosis.
Patient cells show increased γH2AX foci, indicating elevated DNA damage.
Mechanistic model: loss of TULP3 disrupts both ciliary signalling and nuclear SIRT1-mediated repair, converging on tissue fibrosis (liver > kidney > heart).
TULP3