CEP164 – Senior-Loken syndrome

Senior-Loken syndrome (SLSN) is an autosomal recessive ciliopathy characterized by early-onset retinopathy (HP:0000488), nystagmus (HP:0000639), and nephronophthisis (HP:0000090). Diagnostic panels for SLSN include CEP164 given its role in distal appendage-mediated ciliogenesis, but to date no biallelic CEP164 variants have been reported among 74 probands from 70 unrelated families (PMID:36990420).

In a retrospective case series of 74 SLSN patients, pathogenic variants were detected in CEP290 (61.4%), IQCB1 (28.6%), NPHP1 (4.2%), NPHP4 (2.9%), and WDR19 (2.9%) (PMID:36990420); CEP164 yielded no positive cases, indicating limited clinical genetic evidence. The median age at retinopathy onset was 1 month; nystagmus was the most frequent initial sign in CEP290- and IQCB1-associated cases, while nephronophthisis often presented later (median age 9 years) in other genotypes (PMID:36990420).

Functional studies demonstrate that CEP164 is essential for recruiting Tau tubulin kinase-2 (TTBK2) to the mother centriole and initiating ciliogenesis. TTBK2 variants defective for CEP164 binding fail to remove CP110 and cannot rescue ciliogenesis in TTBK2-depleted cells, whereas wild-type TTBK2 restores both CP110 removal and axoneme formation (PMID:25297623). Further, TTBK2 phosphorylates CEP164 and modulates its interaction with Dishevelled-3 in a kinase-dependent manner (PMID:25297623).

The absence of reported CEP164 variants in large SLSN cohorts limits its genetic evidence to a Limited category, despite compelling functional data supporting a haploinsufficiency mechanism. Additional targeted sequencing and variant interpretation in SLSN patients are needed to establish pathogenic CEP164 alleles.

Key Take-home: CEP164 plays a critical role in ciliogenesis and warrants inclusion in genetic testing panels for suspected Senior-Loken syndrome, although current patient-level variant evidence remains limited.

References

• Unknown • n.d. • Senior-Loken syndrome retrospective case series PMID:36990420
• Genes to cells : devoted to molecular & cellular mechanisms • 2014 • Binding to Cep164, but not EB1, is essential for centriolar localization of TTBK2 and its function in ciliogenesis. PMID:25297623

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