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UBAP1 mutations cause juvenile-onset hereditary spastic paraplegias (SPG80) and impair UBAP1 targeting to endosomes.

J Hum Genet. 2019 Nov;64(11):1055-1065. Epub 2019 Sep 12
Haitian Nan 1 , Yuta Ichinose 1 , Masaki Tanaka 2 , Kishin Koh 1 , Hiroyuki Ishiura 3 , Jun Mitsui 4 , Heisuke Mizukami 5 , Masafumi Morimoto 6 , Shun Hamada 7 , Toshihisa Ohtsuka 7 , Shoji Tsuji 4 , Yoshihisa Takiyama 8
Haitian Nan 1 , Yuta Ichinose 1 , Masaki Tanaka 2 , Kishin Koh 1 , Hiroyuki Ishiura 3 , Jun Mitsui 4 , Heisuke Mizukami 5 , Masafumi Morimoto 6 , Shun Hamada 7 , Toshihisa Ohtsuka 7 , Shoji Tsuji 4 , Yoshihisa Takiyama 8
+ et al

[No authors listed]

Author information
  • 1 Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.
  • 2 Institute of Medical Genomics, International University of Health and Welfare, Chiba, 286-8686, Japan.
  • 3 Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-8655, Japan.
  • 4 Department of Molecular Neurology, University of Tokyo, Graduate School of Medicine, Tokyo, 113-8655, Japan.
  • 5 Department of Neurology, Yokohama City Seibu Hospital, St. Marianna University School of Medicine, Yokohama, 241-0811, Japan.
  • 6 Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, 602-8566, Japan.
  • 7 Department of Biochemistry, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan.
  • 8 Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, 409-3898, Japan. ytakiyama@yamanashi.ac.jp.

摘要


We aimed to find a new causative gene and elucidate the molecular mechanisms underlying a new type of hereditary spastic paraplegia (HSP). Patients with HSP were recruited from the Japan Spastic Paraplegia Research Consortium Exome sequencing of genomic DNA from patients in four families was carried out, followed by Sanger sequencing of the UBAP1 gene. A mouse homolog of one UBAP1 frameshift mutation carried by one of the patients was created as a disease model. Functional properties of the UBAP1 wild type and UBAP1-mutant in mouse hippocampus neurons were examined. We identified three novel heterozygous loss of function mutations (c.425_426delAG, c.312delC, and c.535G>T) in the UBAP1 gene as the genetic cause of a new type of HSP (SPG80). All the patients presented identical clinical features of a pure type of juvenile-onset HSP. Functional studies on mouse hippocampal neurons revealed that the C-terminal deletion UBAP1-mutant of our disease model had lost its ability to bind ubiquitin in vitro. Overexpression of the UBAP1 wild type interacts directly with ubiquitin on enlarged endosomes, while the UBAP1-mutant cannot be recruited to endosome membranes. Our study demonstrated that mutations in the UBAP1 gene cause a new type of HSP and elucidated its pathogenesis. The full-length UBAP1 protein is involved in endosomal dynamics in neurons, while loss of UBAP1 function may perturb endosomal fusion and sorting of ubiquitinated cargos. These effects could be more prominent in neurons, thereby giving rise to the phenotype of a neurodegenerative disease such as HSP.