UBAP1 – Spastic Paraplegia 80 (SPG80)

Hereditary spastic paraplegias are a group of rare neurodegenerative disorders characterized by progressive spastic paraparesis. Spastic paraplegia 80 (SPG80) is an autosomal dominant form linked to heterozygous mutations in UBAP1 and classified as spastic paraplegia 80, autosomal dominant.

Genetic studies have identified truncating UBAP1 variants in SPG80 probands. A novel heterozygous c.279del (p.Ser94ValfsTer9) variant segregated in eight affected members of a single family (PMID:32222895). Exome sequencing in four additional families revealed three loss-of-function variants, including c.535G>T (p.Glu179Ter) (PMID:31515522).

Subsequent analyses in five unrelated families uncovered a recurrent two-base-pair deletion c.426_427del (p.Lys143SerfsTer15) present in four families and a de novo c.475_476delTT (p.Phe159Ter) in another (PMID:31696996). Two more truncating alleles, c.468_469del (p.Ala157_Gly186del) and c.512T>G (p.Leu171Ter), were described in two families (PMID:34191852).

All variants are predicted to escape nonsense-mediated decay, yielding truncated UBAP1 proteins lacking ESCRT-I binding domains. Segregation analyses confirm autosomal dominant transmission in at least 10 additional affected relatives (PMID:32222895; PMID:31696996).

Functional assays demonstrate that mutant UBAP1 fails to bind ubiquitin or localize to endosomal membranes, impairing neurite outgrowth in neuronal models (PMID:31515522). A Ubap1+/E176Efx23 knock-in mouse recapitulates progressive hind limb dysfunction, spinal motor neuron loss, and ubiquitin accumulation, mirroring the human phenotype (PMID:35962060).

These findings establish haploinsufficiency of UBAP1 as the pathogenic mechanism underlying autosomal dominant SPG80. Genetic testing for truncating UBAP1 variants is recommended for patients presenting with progressive spastic paraparesis.

References

• Neurogenetics • 2020 • Autosomal dominant hereditary spastic paraplegia caused by mutation of UBAP1. PMID:32222895
• Journal of human genetics • 2019 • UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias (SPG80) and impair UBAP1 targeting to endosomes. PMID:31515522
• Human mutation • 2020 • Truncating variants in UBAP1 associated with childhood-onset nonsyndromic hereditary spastic paraplegia. PMID:31696996
• PLoS one • 2021 • Two novel truncating variants in UBAP1 are responsible for hereditary spastic paraplegia. PMID:34191852
• Journal of human genetics • 2022 • Ubap1 knock-in mice reproduced the phenotype of SPG80. PMID:35962060

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