Submission Details

The STK36 gene encodes serine/threonine kinase 36, also known as Fused, which is essential in vertebrates for the proper formation and function of motile cilia and is involved in regulating the Hedgehog (Hh) signaling pathway (Chen et al., 2005, PMID: 16055716; Murone et al., 2000, PMID: 10806483; Wilson et al., 2009, PMID: 19305393). Although STK36 is dispensable for canonical Hh signaling in mammals, it plays a crucial role in ciliogenesis, particularly in the assembly of the central pair (CP) apparatus within motile cilia (Wilson et al., 2009, PMID: 9305393; Merchant et al., 2005, PMID: 16055717). This gene has been implicated in various developmental processes, including establishing left-right asymmetry and mucociliary clearance (Wilson et al., 2009, PMID: 19305393). STK36 disruption has recently been found in association with primary ciliary dyskinesia 46 (PCD 46, MONDO:0030332), with one patient showing defects in ciliary structure and function (Edelbusch et al., 2017, PMID: 28543983). The patient was described as harboring a homozygous frameshift variant, NM_015690.5(STK36):c.1399del (p.Glu467fs), which results in a premature stop codon in exon 12 of 27, indicating a likely loss-of-function mechanism. The patient presented with typical PCD symptoms, including recurrent sinusitis, otitis, pneumonia, and bronchiectasis. These symptoms may have resulted from impaired mucociliary clearance due to dysfunctional cilia. Pulmonary function tests showed significantly reduced forced vital capacity and forced expiratory volume in 1 second, indicating compromised lung function. Transmission electron microscopy of respiratory epithelial cells from a nasal brush biopsy showed abnormalities of the cilia central pair (CP) apparatus, lacked coordinated movement, and displayed a stiff and reduced beating amplitude (Edelbusch et al., 2017, PMID: 28543983). However, additional PCD patients with biallelic STK36 variants have not yet been reported, reflecting an urgent need for additional genetic evidence.

This gene-disease relationship is also supported by experimental evidence. STK36 mRNA and protein expression across human tissues indicate higher expression in regions such as lung and testis that are associated with the biogenesis of motile cilia, although the expression profile is not highly specific (Murone et al., 2000, PMID: 10806483, proteinatlas.org). Animal models have included a Fu (Fused) knockout (Fu-/-) mouse model (Wilson et al., 2009, PMID: 19305393). Fu is the Drosophila homolog of the STK36 protein, both of which play essential and evolutionarily conserved roles in cellular pathways such as ciliary function and organization (Chen et al., 2005, PMID: 16055716; Murone et al., 2000, PMID: 10806483). The Fu-/- mice show structural defects in the CP microtubules, causing abnormal ciliary multifunctional and impaired fluid flow in the mice trachea and revealing that Fu is essential for the construction of the central pair (CP) apparatus in 9+2 motile cilia (Wilson et al., 2009, PMID: 19305393). Fused knockout mice also show defects in postnatal development, developing a communicating form of hydrocephalus and bilateral suppurative rhinitis with infiltration of neutrophils, reflecting defective mucosal secretions (Merchant et al., 2005, PMID: 16055717). Zebrafish fu morphants similarly show defects in L-R asymmetry and disorganized ciliary axonemal structures, affecting their function and motility, which is rescued by co-injection of mouse fu expression. This demonstrates that Fu plays a conserved role in ciliogenesis, left-right asymmetry, and cilia structures, further connecting Fu's function to phenotypes associated with PCD 46 (Wilson et al., 2009, PMID: 19305393). Stk36 knock-out mice generated using CRISPR/Cas9 technology show features of PCD such as ciliary abnormalities, impaired motility, and hydrocephalus (Christen et al., 2023, PMID: 36786090). Leishmania mexicana studies indicate that ULK4 and Fused/STK36 interact to mediate the assembly of a motile flagellum. The knockout model LmxFused shows ultrastructural defects in CP and abnormalities in outer microtubule doublet number and orientation, resulting in the loss of motile flagella (McCoy et al., 2023, PMID: 36989043). Finally, an Australian Shepherd dog with PCD clinical presentation has been reported by Christen et al., 2023, PMID: 36786090 to harbor a homozygous splicing variant. The dog recapitulates features of the human disease including onset at 10  weeks of age, a history of sneezing, yellow-greenish nasal discharge, recurrent rhinitis with diverse bacterial origins, and TEM results revealing regular ciliary arrangement of variable density with partly irregular arrangement of basal bodies (Christen et al., 2023, PMID: 36786090).

In summary, STK36 has moderate evidence of its association with primary ciliary dyskinesia 46. This association has been presented by a single proband harboring a novel variant in the STK36 gene and is supported by robust data from animal models and functional experimental data without the emergence of contradictory evidence. However, no replication has yet been reported in the form of other human probands, which will be required to reach a higher classification of the gene-disease relationship. This classification was approved by the ClinGen Motile Ciliopathy GCEP on December 5, 2024 (SOP Version 11).