Amplifying the spectrum of SPAST gene mutations

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Hereditary spastic paraplegias (HSPs) are neurodegenerative disorders affecting corticospinal tracts, leading to progressive lower limb spasticity and weakness.
• Spastic paraplegia type 4 (SPG4) is the most prevalent autosomal dominant HSP, typically caused by mutations in the SPAST gene, which encodes the spastin protein (a member of the AAA protein family).

Purpose of the Study:

• To identify and characterize a novel genetic variant in the SPAST gene associated with pure HSP in an Italian family.
• To investigate the functional consequences of the identified variant on the spastin protein.

Main Methods:

• Genetic analysis of an Italian family affected by pure HSP.
• Identification of a heterozygous intragenic microdeletion of 3T in exon 13 of the SPAST gene.
• Analysis of the resulting protein mutation and its conservation across species.

Main Results:

• A novel 3T deletion in exon 13 of the SPAST gene was identified in a heterozygous state.
• This deletion results in a loss of a single leucine residue at position 508 in the spastin protein's AAA ATPase domain.
• The affected amino acid residue is highly conserved across species, suggesting functional importance.
• The identified variant is not documented in public databases.

Conclusions:

• The novel SPAST gene variant is likely pathogenic, leading to a loss-of-function mutation.
• The mutation destabilizes the nucleotide-binding domain of the spastin protein, impairing its function.
• This finding contributes to understanding the genetic basis of SPG4 and related HSPs.