TRAF3IP1 – Senior-Loken Syndrome

Senior-Loken syndrome (SLSN) is an autosomal recessive ciliopathy characterized by early-onset retinopathy and nephronophthisis. A retrospective case series of 74 patients from 70 unrelated families with biallelic variants in ten known SLSN genes did not identify any TRAF3IP1 pathogenic alleles, whereas CEP290 and IQCB1 accounted for >90% of cases (PMID:36990420). This absence of TRAF3IP1 variants across a well-phenotyped cohort supports a limited role in SLSN pathogenesis.

Functional studies in mammalian and model organisms demonstrate that TRAF3IP1 is essential for ciliogenesis and normal hedgehog signaling. Homozygous Traf3ip1 mutant mice exhibit embryonic lethality, polydactyly, neural tube defects, and disrupted ciliary assembly, consistent with a loss-of-function mechanism (PMID:21945076). These data provide moderate experimental support for TRAF3IP1’s involvement in ciliopathies but lack human genetic corroboration.

Overall, the current evidence is classified as Limited for TRAF3IP1–Senior-Loken syndrome association due to absence of reported cases, with Functional evidence at a Moderate level. Additional human genetic studies, including identification of biallelic TRAF3IP1 variants in SLSN patients, are required to establish clinical validity.

Key Take-home: No TRAF3IP1 variants have been observed in Senior-Loken syndrome cohorts, and human genetic evidence remains insufficient despite supportive functional data.

References

• Journal of Medical Genetics • 2023 • Genetic and phenotypic spectrum of Senior-Loken syndrome: a retrospective series PMID:36990420
• Developmental Biology • 2011 • Mutations in Traf3ip1 reveal defects in ciliogenesis, embryonic development, and altered cell size regulation PMID:21945076

Evidence Based Scoring (AI generated)