Gene and protein function
UBAP1encodes Ubiquitin-associated protein 1, a component of the endosomal sorting complex required for transport (ESCRT-I). It is involved in endosomal trafficking and ubiquitin-mediated cargo sorting.
Mutation spectrum
• Nearly all pathogenic variants described to date are heterozygous truncating mutations, typically located in the C-terminal region.
• These variants disrupt the UBA (ubiquitin-associated) domain, impairing protein function.
Pathophysiological mechanism
• Truncated UBAP1 protein interferes with ESCRT-I function, leading to impaired endosomal sorting.
• This disrupts neuronal homeostasis, especially in long corticospinal tract neurons vulnerable to trafficking defects.
Diagnostic testing
• Genetic confirmation is performed via next-generation sequencing (NGS) panels for HSP or whole-exome sequencing.
• Segregation studies are recommended for familial cases.
UBAP1