REEP1 mutations in SPG31: frequency, mutational spectrum, and potential association with mitochondrial...

Area of Science:

• Genetics and Neurology
• Neurodegenerative Diseases
• Molecular Biology

Background:

• Hereditary spastic paraplegias (HSP) are a diverse group of neurodegenerative disorders.
• SPG31, a pure dominant form of HSP, has been linked to mutations in the REEP1 gene.
• Previous research has identified REEP1 as a causative gene for certain HSP subtypes.

Purpose of the Study:

• To investigate the frequency and spectrum of REEP1 mutations in a large cohort of French patients with autosomal dominant hereditary spastic paraplegia (AD-HSP).
• To correlate REEP1 mutations with clinical phenotypes, including pure and complicated forms of AD-HSP.
• To explore potential cellular consequences of REEP1 mutations, such as mitochondrial dysfunction.

Main Methods:

• Sequencing of all REEP1 exons and multiplex ligation-dependent probe amplification (MLPA) for rearrangement detection.
• Analysis of 175 unrelated index patients with AD-HSP, excluding known HSP genes.
• Clinical phenotyping of patients, including neurological examination and assessment of associated symptoms.
• Investigation of mitochondrial network organization and energy production in patient-derived fibroblasts and muscle tissue.

Main Results:

• Twelve different heterozygous REEP1 mutations, including two exon deletions, were identified in 4.5% of the studied French AD-HSP families.
• Mutations were associated with both pure and complex HSP phenotypes.
• Complex phenotypes included axonal peripheral neuropathy (observed in 5/11 patients), cerebellar ataxia, tremor, and dementia; one patient presented with Silver-like syndrome.
• Abnormal mitochondrial network organization and defective energy production were observed in fibroblasts of one patient.

Conclusions:

• REEP1 mutations are a significant cause of AD-HSP in the French population, contributing to both pure and complex forms.
• The study expands the known mutation spectrum and phenotypic variability associated with REEP1 in HSP.
• Mitochondrial anomalies may play a role in the pathogenesis of REEP1-associated HSP, although the direct link requires further investigation.