Two novel truncating variants in UBAP1 are responsible for hereditary spastic paraplegia

Abstract

Hereditary spastic paraplegias (HSPs) are a group of rare neurodegenerative disorders. HSPs are complex disorders and are clinically and genetically heterogeneous. To date, more than 80 genes or genetic loci have been reported to be responsible for HSPs in a Mendelian-dependent manner. Most recently, ubiquitin-associated protein 1 (UBAP1) has been recognized to be involved in HSP. Here, we identified novel protein truncating variants in two families with pure form of HSP. A novel deletion (c.468_469delTG) in the UBAP1 gene was found in the first family, whereas a nonsense variant (c.512T>G) was ascertained in the second family. The variants were confirmed in all patients but were not detected in unaffected family members. The mutations resulted in truncated proteins of UBAP1. The variants did not result in different subcellular localizations in neuro-2a cells. However, each of the two variants impaired neurite outgrowth. Taken together, our findings expand the pathogenic spectrum of UBAP1 variants in HSP.

Novel Frameshift Heterozygous Mutation in UBAP1 Gene Causing Spastic Paraplegia-80: Case Report With Literature Review

“…According to results reported before, brain MRI was normal in most patients except for one who presented with mild generalized cortical-subcortical volume loss. Moreover, electromyography results of all the patients were normal (6)(7)(8)(9)(12)(13)(14). The clinical features of SPG80 probands with UBAP1 mutations are summarized in Figure 2.…”

“…To date, a total of twenty heterozygous UBAP1 mutations have been identified among 91 patients from 35 families worldwide and diagnosed as SPG80 (including this one). Nineteen mutations (c.247_248insGTGAATTC, c.279delG, c.286_290dupCCAGA, c.295dupG, c.312delC, c.324_325delCA, c.361dupC, c.373C>T, c.382delA, c.425_426delAG, c.426_427delGA, c.436_437insTGAG, c.468_469delTG, c.437dupG, c.475_476delTT, c.512T>G, c.526G>T, c.535G>T, and c.1091delC) have been reported ( 6 – 9 , 12 – 14 ), while our mutation (c.371dupT) was undocumented before ( Figure 1F ). Among the 20 mutations, 16 were frameshift ones identified in 67 patients, of which 53 showed a pure type, 12 showed a complicated type, and 2 were asymptomatic cases.…”

“…The UBAP1 gene encodes the UBAP1 protein, a 502-amino-acid-residue peptide ( 14 ). The UBAP1 protein is a subunit of the endosomal sorting complex required for transport-I (ESCRT-I), which comprises TSG101, VPS28, VPS37A, and MVB12 ( 15 , 16 ).…”

A novel UBAP1 truncated variant in a Chinese family with hereditary spastic paraplegia

“…To date, 18 UBAP1 variants including the one identified here have been described (Bian et al, 2021;Bourinaris et al, 2020;Gu et al, 2020;Wang et al, 2020), and 17 of them occurred in Exon 4 of UBAP1 (Figure 1g), implying that Exon 4 is a potential hotspot region of UBAP1. In addition, all identified variants preserve the UMA domain but cause a loss of the SOUBA domain, implying that loss of ubiquitin binding would be detrimental.…”

A novel mutation in the UBAP1 gene causing hereditary spastic paraplegia: A case report and overview of the genotype-phenotype correlation

“…It was also found that UBAP1 interacted with Toll/interleukin 1 receptor (TIR) domain-containing protein of Pseudomonas aeruginosa , and played a major role in virulence of bacterial pathogens Imbert et al (2017) . Recently, the mutations in UBAP1 were found to cause the pure or complex HSP with autosomal dominant inheritance ( Farazi Fard et al, 2019 ; Lin et al, 2019 ; Nan et al, 2019 ; Bourinaris et al, 2020 ; Gu et al, 2020 ; Wang et al, 2020 ; Bian et al, 2021 ). Therefore, UBAP1 was known as the pathogenic gene of spastic paraplegia-80 (SPG80, OMIM No.…”