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Biallelic pathogenic variants in TULP3 cause an autosomal recessive ciliopathy, hepatorenocardiac degenerative fibrosis, marked by early-onset hepatic fibrosis, fibrocystic kidney disease, cardiomyopathy and neurological features. Two unrelated children presented between 2015 and 2023 with neonatal cholestasis progressing to liver fibrosis (one requiring transplant at age 2), intellectual disability, attention deficit hyperactivity disorder, portal hypertension or abnormal cranial imaging (PMID:40579123). Each harbored compound heterozygous variants: one carried c.73C>T (p.Gln25Ter) and c.1211T>G (p.Met404Arg), the other c.666T>G (p.Tyr222Ter) and c.1291G>C (p.Gly431Arg).
Functional studies in patient-derived cells demonstrate that the nonsense alleles undergo predicted nonsense-mediated decay, Met404Arg abolishes TULP3 expression, and Gly431Arg disrupts ciliary localization of TULP3 and trafficking of ARL13B and INPP5E, resulting in impaired ciliogenesis and loss-of-function (PMID:40579123). These data support a recessive loss-of-function mechanism. Screening for TULP3 variants is recommended in early-onset hepatic fibrosis with neurological involvement.
Gene–Disease AssociationLimitedTwo unrelated probands with biallelic deleterious TULP3 variants and concordant functional assays ([PMID:40579123]) Genetic EvidenceLimitedTwo probands with compound heterozygous loss-of-function and missense variants in TULP3 ([PMID:40579123]) Functional EvidenceModerateIn vitro assays show nonsense-mediated decay, loss of TULP3 expression, impaired ciliary trafficking and ciliogenesis ([PMID:40579123]) |