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A Japanese familial spastic paraplegia associated with a missense UBQLN2 variant

Journal of Human Genetics volume 70, pages 645–648 (2025)Cite this article

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Abstract

UBQLN2 is located on Xp11.21 and encodes the ubiquilin 2 protein involved in protein homeostasis. Heterozygous or hemizygous missense variants in UBQLN2 cause amyotrophic lateral sclerosis (ALS). In addition, rare cases of primary lateral sclerosis (PLS) and spastic paraplegia (SPG) associated with UBQLN2 variants have also been reported. Here, we report four male patients in a family with SPG carrying a hemizygous missense UBQLN2 variant (NM_013444.4:c.1442G>T, p.(Gly481Val)). These patients showed childhood-onset lower limb spasticity, progressing to gait disturbance. The mean onset age (11 years) was earlier than that of previous ALS (49.6 years), SPG (29 years) and PLS (25.5 years) cases, and their progression was slower than in ALS or PLS. Literature review reveals Pro506 missense variants are associated with various motor neuron disease phenotypes, with some SPG patients progressing to ALS. Therefore, we consider that careful follow-up is warranted for UBQLN2-related SPG patients.

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Fig. 1: A schematic of the UBQLN2 protein structure, pedigree and results of Sanger sequencing, brain MRI, and interspecies conservation of the UBQLN2 protein amino acid sequence.
Fig. 2: Figure of the clinical and treatment course.

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The authors confirm that the data supporting the findings of this study are available within the article or its supplementary material.

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Acknowledgements

This work was supported in part by the Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research (B) (Grant number JP23K27566 for H.S.), the Japan Agency for Medical Research and Development (AMED) (JP25ek0109760, JP25ek0109674, and JP25ek0109637 for H.S.), the Takeda Science Foundation, and HUSM Grant-in-Aid from Hamamatsu University School of Medicine.

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Authors and Affiliations

  1. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Kazuki Watanabe, Mitsuko Nakashima & Hirotomo Saitsu

  2. Department of Neurology, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Kazuki Watanabe

  3. Department of Neurology, Shizuoka Children’s Hospital, Shizuoka, Japan

    Tatsuya Ema

  4. Department of Clinical Genetics and Cytogenetics, Shizuoka Children’s Hospital, Shizuoka, Japan

    Kenji Shimizu & Kosuke Yamada

Authors
  1. Kazuki Watanabe
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  2. Tatsuya Ema
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  3. Kenji Shimizu
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  4. Kosuke Yamada
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  5. Mitsuko Nakashima
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Correspondence to Mitsuko Nakashima or Hirotomo Saitsu.

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Watanabe, K., Ema, T., Shimizu, K. et al. A Japanese familial spastic paraplegia associated with a missense UBQLN2 variant. J Hum Genet 70, 645–648 (2025). https://doi.org/10.1038/s10038-025-01392-4

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