Abstract: Alström Syndrome (AS) is an autosomal recessive rare disorder caused by mutations in ALMS1, a protein localized to centrosomes and basal bodies of cilia, which are pathologically affected in AS patients. Although previously demonstrate normal intelligence, increasing evidences indicate involvement of ALMS1 mutation in brain symptoms, including autism-spectrum behavior, seizure, obsessive compulsive, psychotic behaviors and so on. However, the underlying molecular mechanisms underlying the neurologic pathologies have never been elucidated. Here, we established two human induced pluripotent stem cell (hiPSC) lines with ALMS1 mutations from AS patients. We also generated isogenic control with CRISPR-Cas9-mediated mutant gene correction and ALMS1 gene knockout lines. The hiPSCs and control lines were then differentiated into cerebral organoids. We identified that ALMS1gene mutation caused complete loss of ALMS1protein, resulting in abnormally elongated primary cilia in human neural progenitor cells (hNPCs), which was rescued by gene correction. By establishing starvation and recovery method, patient NPCs exhibited obvious disruption of cilium disassembly. These NPCs, subsequently displayed reduced cell proliferation and increased cell cycle exit due to shorter cell cycle length. Single-cell transcriptomic profiling of patient derived brain organoid demonstrated significantly decreased autophagy and ubiquitination in the neuroblasts caused by ALMS1 mutation, suggesting abnormal development of patient derived NPCs. Our work elucidates the pivotal role of ALMS1 in human brain development, providing an important foundation for the treatment of this disease.
Funding Source: National Natural Science Foundation
