Stop-gain mutations in UBAP1 cause pure autosomal-dominant spastic paraplegia

Abstract

Hereditary spastic paraplegias refer to a heterogeneous group of neurodegenerative disorders resulting from degeneration of the corticospinal tract. Clinical characterization of patients with hereditary spastic paraplegias represents progressive spasticity, exaggerated reflexes and muscular weakness. Here, to expand on the increasingly broad pools of previously unknown hereditary spastic paraplegia causative genes and subtypes, we performed whole exome sequencing for six affected and two unaffected individuals from two unrelated Chinese families with an autosomal dominant hereditary spastic paraplegia and lacking mutations in known hereditary spastic paraplegia implicated genes. The exome sequencing revealed two stop-gain mutations, c.247_248insGTGAATTC (p.I83Sfs*11) and c.526G>T (p.E176*), in the ubiquitin-associated protein 1 (UBAP1) gene, which co-segregated with the spastic paraplegia. We also identified two UBAP1 frameshift mutations, c.324_325delCA (p.H108Qfs*10) and c.425_426delAG (p.K143Sfs*15), in two unrelated families from an additional 38 Chinese pedigrees with autosomal dominant hereditary spastic paraplegias and lacking mutations in known causative genes. The primary disease presentation was a pure lower limb predominant spastic paraplegia. In vivo downregulation of Ubap1 in zebrafish causes abnormal organismal morphology, inhibited motor neuron outgrowth, decreased mobility, and shorter lifespan. UBAP1 is incorporated into endosomal sorting complexes required for transport complex I and binds ubiquitin to function in endosome sorting. Patient-derived truncated form(s) of UBAP1 cause aberrant endosome clustering, pronounced endosome enlargement, and cytoplasmic accumulation of ubiquitinated proteins in HeLa cells and wild-type mouse cortical neuron cultures. Biochemical and immunocytochemical experiments in cultured cortical neurons derived from transgenic Ubap1flox mice confirmed that disruption of UBAP1 leads to dysregulation of both early endosome processing and ubiquitinated protein sorting. Strikingly, deletion of Ubap1 promotes neurodegeneration, potentially mediated by apoptosis. Our study provides genetic and biochemical evidence that mutations in UBAP1 can cause pure autosomal dominant spastic paraplegia.

Novel CAPN1 mutations extend the phenotypic heterogeneity in combined spastic paraplegia and ataxia

“…This retrospective study was carried out at the Department of Neurology of the First Affiliated Hospital of Fujian Medical University. In total, 240 families that fulfilled Fink’s diagnostic criteria for HSP symptoms were enrolled irrespective of their genetic diagnosis 1,2,25‐27 . Clinical features, brain MRI findings, and genetic data were collected and analyzed for each available case.…”

“…In total, 240 families that fulfilled Fink's diagnostic criteria for HSP symptoms were enrolled irrespective of their genetic diagnosis. 1,2,[25][26][27] Clinical features, brain MRI findings, and genetic data were collected and analyzed for each available case. The ethics committees of the First Affiliated Hospital of Fujian Medical University approved the study, and written informed consent was obtained from each of the participants.…”

“…Subsequently, point mutations and small indel (insertion/deletion) mutations (< 50 base pairs) in 82 known HSP-causative genes (https://neuromuscular.wustl.edu) were screened by targeted next-generation sequencing (NGS) or whole-exome sequencing (WES) using the Illumina HiSeq 3000 platform. [25][26][27][28] The pathogenicity of the filtered variants was then investigated by in silico prediction tools. The variants were finally comprehensively classified according to the American College of Medical Genetics and Genomics (ACMG) criteria.…”

Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

“…While we were conducting this study, truncating UBAP1 variants were reported in HSP families of diverse geographic origin, including the three variants we are reporting in this study [4,[12][13][14]. Thus far, and including our study, 30 families with AD HSP have been reported (Supplementary Table 1).…”

Rethinking monogenic neurological diseases

“…Many brain diseases progress relatively slowly, arising from a long term process that starts with subtle molecular dysregulation and proceeds to the cellular and tissue levels before manifesting as clinical symptoms. 12 Given the single genetic causal factors underlying monogenic neurological disorders, it is possible to conduct longitudinal observation of patients as well as use experimental models, including cell models, rodent models, and even non-human primate models. Imagine, for example, a family with a monogenic neurological disorder in which the first case is a father, who develops symptoms needing medical attention at the age of 60.…”