Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia

Area of Science:

• Neurogenetics
• Molecular Neuroscience
• Movement Disorders

Background:

• Dystonia is a severe hyperkinetic movement disorder often inherited as a monogenic trait.
• The presynaptic active zone plays a crucial role in neurotransmission and motor control.

Purpose of the Study:

• To identify the genetic basis of autosomal recessive dystonia.
• To investigate the role of the active-zone RIM-binding protein 1 (RIMBP1) in dystonia pathogenesis.

Main Methods:

• Genetic analysis of affected individuals from three families.
• In vitro and in vivo studies using mouse models.
• Electrophysiological and imaging techniques to analyze neurotransmission.

Main Results:

• Identified homozygous variants in TSPOAP1 (encoding RIMBP1) as a cause of dystonia.
• Loss-of-function variants led to juvenile-onset generalized dystonia, intellectual disability, and cerebellar atrophy.
• A specific missense variant (p.Gly1808Ser) caused adult-onset focal dystonia.
• RIMBP1 deficiency in mice resulted in motor abnormalities and cerebellar changes.
• The p.Gly1808Ser variant enhanced neurotransmission, suggesting dual mechanisms in disease.

Conclusions:

• Establishes a direct link between presynaptic active zone dysfunction and dystonia.
• Demonstrates that both reduced and enhanced neurotransmission can lead to dystonia.
• Highlights RIMBP1 as a key player in motor control and neurotransmission balance.