TTC8 – Bardet-Biedl Syndrome

TTC8 (BBS8) encodes a core subunit of the BBSome complex essential for primary cilium assembly and function. Bardet-Biedl syndrome is a multisystem, autosomal recessive ciliopathy characterized by polydactyly, obesity, retinal dystrophy, intellectual disability, hypogonadism and renal anomalies. Pathogenic variants in TTC8 account for a minority of BBS cases yet have been reported in multiple unrelated families, confirming TTC8 as a bona fide BBS gene.

Genetic Evidence

Autosomal recessive inheritance of biallelic TTC8 variants has been demonstrated in at least five unrelated families. Two splice-site and three nonsense/frameshift mutations have been observed in consanguineous and outbred pedigrees ([PMID:16308660]; [PMID:16877420]). A recurrent loss-of-function variant, c.680G>A (p.Trp227Ter), segregates with disease in two independent families, supporting high penetrance of TTC8 truncating alleles in BBS ([PMID:16877420]).

Variant Spectrum

Reported TTC8 variants are predominantly loss-of-function, including nonsense, frameshift and essential splice-site changes. The exemplar variant c.680G>A (p.Trp227Ter) occurs in exon 7, leading to premature truncation of BBS8 and predicted nonsense-mediated decay. No hypomorphic or deep-intronic alleles have been convincingly associated with isolated BBS to date.

Functional Evidence

Ttc8 knockout mice develop late-onset cystic kidney disease with reduced acetylation of ciliary α-tubulin and increased HDAC2 activity, recapitulating renal pathology seen in human BBS ([PMID:40667253]). In a separate model, BBS8-deficient mice exhibit severe photoreceptor outer segment defects and progressive rod/cone degeneration, linking TTC8 loss to retinal dystrophy ([PMID:29126234]). These concordant in vivo assays confirm the critical role of TTC8 in ciliary stability and sensory neuron function.

Mechanism and Disease Convergence

Loss of TTC8 disrupts BBSome assembly, impairs trafficking within the primary cilium and leads to pleiotropic organ dysfunction. Haploinsufficiency is not observed; disease manifests only with biallelic inactivation. The combination of human genetic and animal model data supports a loss-of-function mechanism underpinning TTC8-related BBS.

Key Take-home

TTC8 (BBS8) is a confirmed autosomal recessive BBS gene; targeted sequencing of TTC8 should be included in diagnostic panels for patients presenting with core features of Bardet-Biedl syndrome. Genetic confirmation enables precise counseling, anticipatory management and potential future gene- or pathway-directed therapies.

References

• Journal of human genetics • 2006 • BBS8 is rarely mutated in a cohort of 128 Bardet-Biedl syndrome families. PMID:16308660
• Investigative ophthalmology & visual science • 2006 • Screening of the eight BBS genes in Tunisian families: no evidence of triallelism. PMID:16877420
• bioRxiv • 2025 • Loss of Bbs8 leads to cystic kidney disease in mice with reduced acetylation of ciliary alpha-tubulin through HDAC2. PMID:40667253
• Human molecular genetics • 2018 • Bardet-Biedl syndrome-8 (BBS8) protein is crucial for the development of outer segments in photoreceptor neurons. PMID:29126234

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