PMC9344137_01
The pedigree of HSP with UBAP1 mutation. (A) The inheritance pattern in this family showed classic autosomal dominant inheritance. HSP patients are marked by black symbols. An arrow indicates the proband. The genotypes of all available family members are displayed with c.279delG mutation and wild typeallele. (B) Alignment of Sanger sequencing results showed c.437dupG induced mRNA frameshift of UBAP1 gene. The c.437dupG (red arrow) was detected in patients, but not in healthy members, which showed the mutation is the co-segregation with the manifestations in the family. Notes:Mut, Mutation; WT, wild type.
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F1
The family tree showed an autosomal dominant pattern of inheritance (Figure1A). By Sanger sequencing (Figure 1B), we confirmed that the mutation of UBAP1 was present in other patients of the family (IV-2 and IV-3) but not in the normal individuals (III-1 and IV-1), suggesting that there is a co-segregation between the mutation and the manifestations of the patients. Comparing the structures of UBAP1 wild-type and truncated proteins, it was found that the truncated protein retains a partially similar structure to the wild-type protein only at the N-terminus (Supplementary Figure S1).
Brain and spine MRI of the patients in the HSP family. (A) Axial T2-weighted images and sagittal T1-weighted images of patients. The hyperintensity on the left corticospinal tract pathways were present in proband (V-1). The patient IV-2 and IV-3 showed the bilateral hyperintensities (white arrows). The subjects in this family did not have signs of corpus callosum atrophy. (B) MR image of proband (V-1) showed an oval space-occupying lesion with well-defined boundary in the spinal canal at the corresponding to L4-5 level (white asterisk). (B1) Sagittal T2WI; (B2) Sagittal fat-suppressed T2WI; (B3) Sagittal T1WI; (B4) Axial T2WI. The abnormal signal shadow was uniformity hyperintense signal on T2WI, while no signal reduction on fat-suppressed T2WI (B2). The shadow showed nonuniform and inhomogeneous signals on T1WI(B3). The dural sac was partially compressed in B4 (white arrows). Sagittal T2WI: T2-weighted Imaging; T1WI: T1-weighted Imaging.
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F2
Brain magnetic resonance imaging (MRI) of the proband revealed the right hyperintense signal on corticospinal tract pathways, and the patients IV-2 and IV-3 showed the bilateral hyperintensities (Figure 2A). It is worth noting that the spinal MRI of the proband revealed a dermoid cyst at the lumbar 4-5 level of the spinal cord (Figure 2B, asterisk), which was located at the area of the previous surgical resection. T2WI (Figure 2B1), high signal intensity on fat-suppressed T2WI (Figure 2B2), slightly higher signals on T1WI (Figure 2B3) and the majority of the signals were uniform and well defined. The boundary of the lesion was clear and the dural sac was partially compressed (Figure 2B4). European patients [9.01 (95%CI = 5.61-12.42) in the random-effects model] were younger than Asian patients [11.66 (95%CI = 9.95-13.36) in the random-effects model] (Supplementary Figure S2).
Schematic diagram of reported mutations and clinical features of UBAP1-related HSP. (A) The five transcripts of UBAP1 from the database of NCBI RefSeq. All of reported mutations in UBAP1 were displayed in the transcript NM_016,525 (B) and UBAP1 protein (C). The numbers in lollipop represents the mutation number. The mutation found in our study was marked in red. (D) Phenotypic heterogeneity was observed in HSP patients with UBAP1 mutated. The lower limb (LL) hyperreflexia and spasticity, positive Babinski sign were the main symptoms in patients with UBAP1 mutation. Nearly one quarter of patients suffered from bladder and upper extremity muscle reflexes.
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F3
The c.437dupG was predicted to lead to a reading frame shift at position 146 and a stop codon (p.Ser146ArgfsTer13), with a concomitant 70.9% reduction in protein length (Figure3B). The lower limb (LL) spasticity and hyperreflexia, positive Babinski sign were the main complications of UBAP1-related HSP (Figure 3D). At present, 20 mutations in UBAP1 have been found in HSP patients, nineteen of which were located in exon 4 Figure 3A, and only c.1091delC was in exon 5. These variation types included insertion, duplication, and nonsense (Figure 3B). All reported mutations produced the truncate UBAP1 protein and the loss of the UBA (UBAP1-MVB12-associated) domain, which were supposed to lead to dominant-negative (DN) UBAP1 proteins (Figure 3C).