Heterogeneous clinical phenotypes and cerebral malformations reflected by rotatin cellular dynamics

Area of Science:

• Genetics and Developmental Neuroscience
• Cell Biology and Molecular Medicine

Background:

• Recessive mutations in RTTN, encoding rotatin, are linked to polymicrogyria and other brain malformations.
• The precise function of rotatin in brain development and the molecular mechanisms of these malformations remain unclear.

Purpose of the Study:

• To elucidate the function of rotatin in brain development and understand the pathogenesis of RTTN-associated cerebral malformations.
• To correlate genotype with phenotype and investigate the cellular and molecular consequences of RTTN mutations.

Main Methods:

• Clinical review of 28 cases with RTTN mutations and analysis of affected individuals' skin fibroblasts.
• In vitro RTTN expression in HEK293T cells, high-resolution immunomicroscopy, flow cytometry, and proteomics analysis.
• Functional studies in human induced pluripotent stem cell-derived neurons.

Main Results:

• A core phenotype of intellectual disability, microcephaly, and cortical malformations was identified, with severity correlating to residual protein function.
• Mutant cells exhibit cell cycle dysregulation, mitotic failure, centrosome amplification, multipolar spindles, aneuploidy, and apoptosis.
• Rotatin is crucial for primary cilia maintenance and interacts with myosin motors, highlighting its role in neuronal migration.

Conclusions:

• Rotatin plays a critical role in both cell cycle progression and neuronal migration during brain development.
• Dysfunction of rotatin leads to heterogeneous cerebral malformations due to defects in neuronal proliferation and migration.
• Understanding rotatin's multifaceted functions provides insights into the pathogenesis of complex neurodevelopmental disorders.