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ORIGINAL RESEARCH article
Front. Neurosci.
Sec. Neurodegeneration
Volume 18 - 2024 |
doi: 10.3389/fnins.2024.1437668
This article is part of the Research Topic Neurodegenerative Diseases and Gangliosides View all 6 articles
Functional evaluation of novel variants of B4GALNT1 in a patient with hereditary spastic paraplegia and the general population
Provisionally accepted- 1 Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
- 2 Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan
- 3 Center for Medical Genetics, Shinshu University Hospital, Matsumoto, Japan
- 4 Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
- 5 Department of Pharmacy, Juntendo University, Urayasu, Chiba, Japan
- 6 Institute for Environmental and Gender-Specific Medicine, Juntendo University, Urayasu, Chiba, Japan
- 7 Department of Otorhinolaryngology - Head and Neck Surgery, School of Medicine, Shinshu University, Matsumoto, Nagano, Japan
- 8 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
- 9 Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan
- 10 Division of Structural Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
- 11 Glycan and Life System Integration Center, Soka University, Hachioji, Tōkyō, Japan
- 12 Institute for Glyco-core Research (iGCORE), Nagoya University, Nagoya, Japan
- 13 Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan
- 14 Matsumoto City Hospital, Matsumoto, Nagano, Japan
- 15 Other, Gifu, Japan
- 16 Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan
- 17 Forefront Research Center, Graduate School of Science, Osaka University, Toyonaka, Japan
Hereditary spastic paraplegia (HSP) is a heterogeneous group of neurological disorders that are characterized by progressive spasticity and weakness in the lower limbs. SPG26 is a complicated form of HSP, which includes not only weakness in the lower limbs, but also cognitive impairment, developmental delay, cerebellar ataxia, dysarthria, and peripheral neuropathy, and is caused by biallelic mutations in the B4GALNT1 gene. The B4GALNT1 gene encodes ganglioside GM2/GD2 synthase (GM2S), which catalyzes the transfer of N-acetylgalactosamine to lactosylceramide, GM3, and GD3 to generate GA2, GM2, and GD2, respectively. The present study attempted to characterize a novel B4GALNT1 variant (NM_001478.5:c.937G>A p.Asp313Asn) detected in a patient with progressive multi-system neurodegeneration as well as deleterious variants found in the general population in Japan. Peripheral blood T cells from our patient lacked the ability for activationinduced ganglioside expression assessed by cell surface cholera toxin binding. Structural predictions suggested that the amino acid substitution, p.Asp313Asn, impaired binding to the donor substrate UDP-GalNAc. An in vitro enzyme assay demonstrated that the variant protein did not exhibit GM2S activity, leading to the diagnosis of HSP26. This is the first case diagnosed with SPG26 in Japan. We then extracted ten novel missense variants of B4GALNT1 from the whole-genome reference panel jMorp (8.3KJPN) of the Tohoku Medical Megabank Organization, which were predicted to be deleterious by Polyphen-2 and SIFT programs. We performed a functional evaluation of these variants and demonstrated that many showed perturbed subcellular localization. Five of these variants exhibited no or significantly decreased GM2S activity with less than 10% activity of the wild-type protein, indicating that they are carrier variants for HSP26. These results provide the basis for molecular analyses of B4GALNT1 variants present in the Japanese population and will help improve the molecular diagnosis of patients suspected of having HSP.
Keywords: hereditary spastic paraplegia, Gangliosides, B4galnt1, GM2/GD2 synthase, glycosyltransferase, missense variant
Received: 24 May 2024; Accepted: 10 Jul 2024.
Copyright: © 2024 Inamori, Nakamura, Shishido, Hsu, Nagafuku, Nitta, Ikeda, Yoshimura, Kodaira, Tsuchida, Matsumoto, Uemura, Ohno, Manabe, Yamaguchi, Togayachi, Aoki-Kinoshita, Nishihara, Furukawa, Kaname, Nakamura, Shimohata, Tadaka, Shirota, Kinoshita, Nakamura, Ohno, Sekijima and Inokuchi. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Kei-ichiro Inamori, Tohoku Medical and Pharmaceutical University, Sendai, 981-8558, Miyagi, Japan
Jin-ichi Inokuchi, Forefront Research Center, Graduate School of Science, Osaka University, Toyonaka, Japan
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