Bi-allelic CAMSAP1 variants cause a clinically recognizable neuronal migration disorder

Area of Science:

• Cell Biology
• Neuroscience
• Genetics

Background:

• Non-centrosomal microtubules are vital for neuronal development, requiring stabilization by proteins like CAMSAP family members.
• Microtubule organization is critical for neurite formation, axonal transport, and neuronal migration.

Purpose of the Study:

• To investigate the role of CAMSAP1 in human neurodevelopmental disorders.
• To identify the genetic cause of a syndromic neuronal migration disorder.

Main Methods:

• Exome sequencing in five unrelated families with a recognizable neurodevelopmental disorder.
• Analysis of neural cell rosette lineages derived from affected individuals.
• Phenotypic characterization of Camsap1-null mice.

Main Results:

• Bi-allelic CAMSAP1 loss-of-function variants were identified as the cause of the disorder.
• Clinical features include craniofacial anomalies, microcephaly, severe neurodevelopmental delay, visual impairment, and seizures.
• Neuroradiological findings show lissencephaly, corpus callosum hypoplasia, and brainstem/cerebellar abnormalities.
• Camsap1-null mice exhibit perinatal mortality and high CAMSAP1 expression in developing brain and facial structures.

Conclusions:

• CAMSAP1 is essential for neuronal migration and overall brain development.
• Bi-allelic CAMSAP1 variants cause a distinct, clinically recognizable neurodevelopmental disorder in humans.
• The findings highlight CAMSAP1's fundamental role in both human and mouse neurodevelopment and craniofacial phenotypes.