DHCR7 links cholesterol synthesis with neuronal development and axonal integrity

The DHCR7 enzyme converts 7-DHC into cholesterol. Mutations in DHCR7 can block cholesterol production, leading to abnormal accumulation of 7-DHC and causing Smith–Lemli–Opitz syndrome (SLOS). SLOS is an autosomal recessive disorder characterized by multiple malformations, including microcephaly, intellectual disability, behavior reminiscent of autism, sleep disturbances, and attention-deficit/hyperactivity disorder (ADHD)-like hyperactivity. Although 7-DHC affects neuronal differentiation in ex vivo experiments, the precise mechanism of SLOS remains unclear. We generated Dhcr7 deficient (dhcr7−/−) zebrafish that exhibited key features of SLOS, including microcephaly, decreased neural stem cell pools, and behavioral phenotypes similar to those of ADHD-like hyperactivity. These zebrafish demonstrated compromised myelination, synaptic anomalies, and neurotransmitter imbalances. The axons of the dhcr7−/− zebrafish showed increased lysosomes and attenuated autophagy, suggesting that autophagy-related neuronal homeostasis is disrupted. •DHCR7 mutations lead to SLOS due to disrupted cholesterol homeostasis.•Cholesterol decreases, whereas 7-DHC increases in dhcr7−/− zebrafish.•Dhcr7−/− zebrafish show microcephaly, synaptic defects, and ADHD-like hyperactivity.•DHCR7 deficiency disrupts autophagy-related neuronal homeostasis in axons.