UBAP1 – Hereditary Spastic Paraplegia

The association between UBAP1 and hereditary spastic paraplegia is supported by multiple independent studies demonstrating an autosomal dominant pattern of inheritance. Affected individuals present with progressive spastic paraparesis, lower limb hyperreflexia, unsteady gait, and hypertonia. These clinical observations have consistently correlated with the presence of truncating UBAP1 variants, underscoring a robust gene‑disease relationship (PMID:32222895). The studies span both single‐family reports and multi‑patient analyses, enhancing diagnostic confidence.

Evidence from case reports highlights a family in which eight affected individuals segregated a novel heterozygous frameshift mutation, exemplified by the variant c.279delG (p.Ser94ValfsTer9). In addition, multiple reports confirm that further truncating mutations co‑segregate with the HSP phenotype in patients from diverse ethnic backgrounds (PMID:35321509). Such recurrent findings across unrelated families provide strong genetic evidence for the role of UBAP1 in this disorder.

Genetic analyses have revealed a spectrum of pathogenic variants including missense, frameshift, and stop‐gain mutations. In the reviewed literature, the variant c.279delG (p.Ser94ValfsTer9) serves as a representative example, demonstrating the classic loss‑of‑function mechanism. Robust segregation data, with over 10 additional affected relatives identified across studies, further support the genetic contribution of UBAP1 variants to the disease phenotype (PMID:31203368).

Experimental evidence from cellular assays and animal models has elucidated the pathogenic mechanism. Functional studies indicate that truncating mutations impair UBAP1’s role in endosomal sorting and ubiquitin binding, which is critical for neuronal homeostasis. Mouse models carrying analogous mutations exhibit neurodegenerative changes in the spinal cord, recapitulating key aspects of the human phenotype (PMID:31515522, PMID:35962060).

There is no significant conflicting evidence to refute the association; instead, the genetic and functional datasets converge, pointing toward a dominant‐negative or haploinsufficiency mechanism underlying the HSP manifestations. This convergence of independent lines of evidence reinforces the clinical validity of using UBAP1 mutation screening for hereditary spastic paraplegia diagnosis.

In summary, the strong genetic and experimental evidence confirms that UBAP1 mutations, including the representative variant c.279delG (p.Ser94ValfsTer9), are causative for autosomal dominant hereditary spastic paraplegia. This association not only aids in accurate diagnosis and clinical management but also underpins future therapeutic explorations.

References

• Neurogenetics | 2020 | Autosomal dominant hereditary spastic paraplegia caused by mutation of UBAP1 PMID:32222895
• Brain : a journal of neurology | 2019 | Stop-gain mutations in UBAP1 cause pure autosomal-dominant spastic paraplegia PMID:31203368
• Journal of human genetics | 2019 | UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias and impair UBAP1 targeting to endosomes PMID:31515522
• Frontiers in neurology | 2022 | Novel Frameshift Heterozygous Mutation in UBAP1 Gene Causing Spastic Paraplegia-80: Case Report With Literature Review PMID:35321509
• Journal of human genetics | 2022 | Ubap1 knock-in mice reproduced the phenotype of SPG80 PMID:35962060

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