ALPK1

Ciliogenesis screen results (1 screens)

• Breslow et al. 2018 (CRISPR) [CRISPR]: No Significant Effect PMID:29459680

Phenotypes

Human ciliopathy phenotype:

ROSAH Syndrome: Retinal dystrophy with progressive vision loss, Optic nerve oedema, Splenomegaly, Anhidrosis, and Headache. Additional features include recurrent fevers, deforming arthritis, AA amyloidosis, dental anomalies (consistent with ciliopathy dental phenotypes), and basal ganglia/brainstem mineralisation on MRI. Autosomal dominant.

Ciliopathy associations

• ROSAH Syndrome

References: PMID:30967659, PMID:35550555, PMID:34782689

Subcellular localization

basal body, connecting cilium, centriole, spindle pole

References: PMID:41005307, PMID:30967659

Functional category

• Ciliary assembly/disassembly
• Signaling (Hedgehog, GPCRs, ion channels)

Function

ALPK1 encodes alpha-protein kinase 1. Heterozygous gain-of-function missense mutations (recurrent T237M, also Y254C) cause ROSAH Syndrome (Retinal dystrophy, Optic nerve oedema, Splenomegaly, Anhidrosis, Headache; OMIM #614979) — an autosomal dominant ocular multisystem disorder. Patient mutations identified in >20 patients from 12+ unrelated families (Williams 2019 Genet Med, Kozycki 2022, Williams 2022). ALPK1 localizes to the basal body of the connecting cilium of photoreceptors, centrioles, spindle poles during metaphase, and the base of the primary cilium. Patient-derived fibroblasts demonstrate defective ciliogenesis (reduced number of ciliated cells). ALPK1 has a dual role — both ciliary (basal body) and autoinflammatory (NF-κB pathway activation). Anti-TNF, anti-IL-1, and anti-IL-6 (tocilizumab) therapies provide symptomatic relief in patients.