A novel GBA2 gene missense mutation in spastic ataxia

Area of Science:

• Genetics and Molecular Biology
• Neurology
• Rare Diseases

Background:

• Autosomal recessive cerebellar ataxias (ARCA) are a diverse group of rare genetic disorders affecting cerebellar and spinal cord pathways.
• Spastic ataxia presents with a combination of cerebellar and upper motor neuron signs, indicating complex neurological involvement.
• Identifying the genetic basis of rare diseases is crucial for diagnosis, understanding pathogenesis, and developing potential therapies.

Purpose of the Study:

• To identify the causative genetic mutation in a consanguineous Cypriot family presenting with spastic ataxia.
• To investigate the role of the GBA2 gene in the etiology of autosomal recessive cerebellar ataxia.

Main Methods:

• Clinical evaluation of affected family members.
• Genetic analysis including linkage analysis at known ARCA loci and whole-genome SNP homozygosity mapping.
• Whole-exome sequencing of the proband followed by targeted analysis of the mapped chromosomal region.

Main Results:

• Linkage analysis initially suggested the APTX locus, but subsequent investigation ruled out mutations in this gene.
• Whole-genome screening mapped the disease locus to Chromosome 9p21.1-p13.2.
• Whole-exome sequencing identified a novel missense mutation in the GBA2 gene, strongly associated with the spastic ataxia phenotype in the family.

Conclusions:

• A novel GBA2 gene mutation is identified as the cause of spastic ataxia in this consanguineous family.
• This study expands the spectrum of GBA2-associated neurological disorders.
• GBA2 mutations are proposed as a potentially significant genetic cause of autosomal recessive cerebellar ataxia (ARCA).