STK36

Inheritance Pattern: AR

Disease ID:MONDO:0030332

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0030332

Submitter: ClinGen

The *STK36* gene was first reported in association with primary ciliary dyskinesia in 2017, with the identification of a premature stop codon in *STK36* in the homozygous state in one primary ciliary dyskinesia (PCD) patient, specifically primary ciliary dyskinesia 46 (PCD 46), (MONDO:0030332) (Edelbusch et al., PMID: 28543983). The c.1399del (p.Glu467Argfs13) variant is a predicted frameshift and results in a premature stop codon. The patient presented with typical PCD symptoms, including recurrent sinusitis, otitis, pneumonia, and bronchiectasis, potentially resulting from impaired mucociliary clearance due to dysfunctional cilia. The individual's pulmonary function tests showed significantly reduced values: forced vital capacity (FVC) at 34.86% and forced expiratory volume in 1 second (FEV1) at 38%, indicating compromised lung function (PMID: 28543983). Transmission electron microscopy of respiratory epithelial cells obtained by nasal brush biopsy from the affected individual and healthy controls revealed abnormalities of the cilia central pair (CP) apparatus, lack of coordinated movement, and display of a stiff and reduced beating amplitude. No mutation was found in any other previously published PCD gene (PMID: 28543983). This gene-disease relationship is also supported by experimental evidence that *STK36* encodes Serine/Threonine Kinase 36, also known as Fused in vertebrates. STK36 is essential for the proper formation and function of motile cilia and is involved in regulating the Hedgehog (Hh) signaling pathway in animal models (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: 19305393; Merchant et al., 2005, PMID: 16055717). This gene is implicated in various developmental processes, including establishing left-right asymmetry and mucociliary clearance (Wilson et al., 2009, PMID: 19305393). Mutation or disruption in *STK36* is characterized by defects in cilia structure and function. *STK36* is expressed at the mRNA and protein levels in human tissues implicated in biogenesis of motile cilia, such as lung and testis, although it is not highly specific (Murone et al., 2000, PMID: 10806483, proteinatlas.org). Fu is the *Drosophila* ortholog of *STK36*, and both play essential roles in ciliary processes across species. The relationship between Fu and STK36 is rooted in their evolutionary conservation, with Fu in *Drosophila* and STK36 in humans sharing similar functional roles in various cellular pathways, particularly ciliary function and organization (Chen et al., 2005, PMID: 16055716; Murone et al., 2000, PMID: 10806483). Additionally, zebrafish fu morphants show defects in L-R asymmetry and display 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). A Fu (Fused) knockout mouse model (PMID: 19305393) provides evidence that Fu is essential for the construction of the central pair (CP) apparatus in 9+2 motile cilia, and its absence in *Fu-/-* mice leads to structural defects in the CP microtubules, causing abnormal ciliary multifunctional and impaired fluid flow in the trachea (Wilson et al., 2009, PMID: 19305393). Fused knockout mice develop a communicating form of hydrocephalus and bilateral suppurative rhinitis with infiltration of neutrophils, reflecting defective mucosal secretions (PMID: 16055717). An *Stk36* knock-out mouse model developed using CRISPR/Cas9 technology also exhibits features of PCD, including ciliary abnormalities, impaired motility, and hydrocephalus (PMID: 36786090). A *Leishmania Mexicana* model has shown that ULK4 and Fused/STK36 interact to mediate the assembly of a motile flagellum. In *Leishmania mexicana* mutants for LmxULK4 and LmxFused, the knockout (KO) shows abnormalities in motile ciliogenesis and a variety of ultrastructural defects in axonemes affecting both central pair and outer microtubule doublet number and orientation (McCoy et al., 2023, PMID: 36989043). Finally, an Australian Shepherd dog with PCD clinical presentation harbors a homozygous c.2868-1G>A mutation in the *STK36* gene that leads to truncation of 36% of wild-type STK36 (PMID: 36786090). The animal shows onset at 10  weeks of age, sneezing and yellow-greenish nasal discharge, recurrent infectious rhinitis and nasal discharge, and nasal and tracheal mucosa TEM analysis revealing ndistinct or irregular central tubule pairs (PMID: 36786090). In summary, *STK36* has Moderate evidence of association with primary ciliary dyskinesia 46. This association has been presented by a single case of a variant in the *STK36* gene in combination with animal models and functional experimental data without the emergence of contradictory evidence. However, no replication through the emergence of other human probands has yet been reported, so that additional case-level evidence will be required to reach a higher calcification gene-disease association. This classification was approved by the ClinGen Motile Ciliopathy GCEP on December 05, 2024 (SOP version 11).

Inheritance Pattern: AD

Disease ID:MONDO:0016575

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0030332

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0030332

Submitter: Ambry Genetics