Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia.

Area of Science:

• Genetics
• Neuroscience
• Rare Diseases

Background:

• Rare neurodegenerative diseases, like hereditary spastic paraplegia (HSP), present a significant diagnostic challenge.
• Despite advances in gene discovery, many cases remain undiagnosed, even after exome sequencing.

Purpose of the Study:

• To identify the genetic cause of hereditary spastic paraplegia (HSP) in families with a diagnostic gap.
• To investigate the role of UBAP1 in the pathophysiology of HSP.

Main Methods:

• Genetic analysis including linkage analysis and exome sequencing.
• Identification of truncating variants in UBAP1 across 10 diverse families.
• Analysis of mRNA and protein expression in patient-derived fibroblasts.

Main Results:

• Autosomal-dominant mutations in UBAP1 were identified in 10 HSP families of diverse geographic origins.
• Truncating variants in a specific region of UBAP1 were found in affected individuals.
• Fibroblast analysis revealed truncated UBAP1 protein expression, suggesting a dominant-negative effect or haploinsufficiency.

Conclusions:

• UBAP1 is a novel autosomal-dominant gene associated with hereditary spastic paraplegia (HSP).
• UBAP1's role in endosomal trafficking and ubiquitination provides a link to previously implicated HSP pathways.
• This finding advances the understanding of HSP pathophysiology and aids in diagnosing this rare neurodegenerative disease.