HSD17B4

Cilia effects upon perturbation of HSD17B4

Cilia number / % ciliated:

Decreased cilia number

Loss-of-function effect:

Shorter cilia

Ciliogenesis screen results (3 screens)

• Wheway et al. 2015 (siRNA) [siRNA]: Ciliogenesis Defect (z=-3.41) PMID:26167766
• Breslow et al. 2018 (CRISPR) [CRISPR]: No Significant Effect PMID:29459680
• Roosing et al. 2015 (siRNA) [siRNA]: No effect PMID:26595381

Phenotypes

Mouse ciliopathy phenotype:

Hsd17b4-/- mice show growth retardation from week 9, <30% survival by week 12; cerebellar atrophy with malformed lobules and Purkinje cell loss; reduced ciliogenesis and shortened cilia in cerebellar granular and Purkinje layers; rotarod motor deficits at 9 and 11 weeks; renal and hepatic fibrosis; infertility; visual deficits. Acetate (50 mM in drinking water during/after gestation) rescues survival (~70% vs ~30%), cerebellar size, Purkinje cell layer in lobule IV/V, ciliogenesis, GLI2/p-Smad2/3/p-AKT signalling, and motor function. Tubastatin A (HDAC6 inhibitor, 50 mg/kg/day IP for 2 weeks) produces comparable rescue (PMID 40102401).

Human ciliopathy phenotype:

D-bifunctional protein deficiency (DBPD; OMIM 261515) — neonatal-onset peroxisomal disorder with hypotonia, seizures, craniofacial dysmorphism, severe neurodevelopmental impairment, cerebellar atrophy, and progressive loss of hearing and vision. Caused by biallelic HSD17B4 loss-of-function variants (D-BPD types I-III).

Ciliopathy associations

• D-Bifunctional Protein Deficiency

Subcellular localization

cilia associated gene, mitochondria, peroxisome

Functional category

• Ciliary assembly/disassembly
• Metabolism
• Cilia length regulation

Function

Peroxisomal multifunctional enzyme (D-bifunctional protein) catalysing the second and third reactions of peroxisomal β-oxidation. Biallelic pathogenic variants (including c.422_423delAG; G16S in the dehydrogenase domain; N457Y in the hydratase domain) cause D-bifunctional protein deficiency (MIM 261515), an early-onset peroxisomal disorder presenting with hypotonia, seizures, craniofacial dysmorphism, cerebellar atrophy, and loss of hearing and vision. Bae et al. 2025 (PMID 40102401) demonstrated a ciliary mechanism: HSD17B4 depletion impairs primary ciliogenesis in patient-derived fibroblasts, RPE siRNA knockdown, and SH-SY5Y CRISPR-KO cells; disrupts Shh/TGF-β/PDGFRα signalling; and is phenocopied by loss of other β-oxidation enzymes (ABCD1, ACOX1, TYSND1). Mechanism: peroxisomal β-oxidation deficit → cellular acetyl-CoA depletion → HDAC6-mediated α-tubulin deacetylation → ciliary axoneme destabilisation. Hsd17b4-/- mice show growth retardation, cerebellar Purkinje cell loss, motor dysfunction, and reduced cerebellar primary cilia; all rescued by acetate (acetyl-CoA precursor) or HDAC6 inhibition (Tubastatin A).

Model organism evidence