Functional evaluation of novel variants of B4GALNT1 in a patient with hereditary spastic paraplegia and the general population

被引:1
|
作者
Inamori, Kei-ichiro [1 ]
Nakamura, Katsuya [2 ,3 ]
Shishido, Fumi [4 ]
Hsu, Jia-Chen [1 ]
Nagafuku, Masakazu [1 ]
Nitta, Takahiro [1 ,5 ,6 ]
Ikeda, Junji [2 ]
Yoshimura, Hidekane [7 ]
Kodaira, Minori [2 ]
Tsuchida, Naomi [8 ,9 ]
Matsumoto, Naomichi [8 ]
Uemura, Satoshi [10 ]
Ohno, Shiho [11 ]
Manabe, Noriyoshi [11 ]
Yamaguchi, Yoshiki [11 ]
Togayachi, Akira [12 ]
Aoki-Kinoshita, Kiyoko F. [12 ]
Nishihara, Shoko [12 ]
Furukawa, Jun-ichi [13 ]
Kaname, Tadashi [14 ]
Nakamura, Masahiko [15 ]
Shimohata, Takayoshi [16 ]
Tadaka, Shu [17 ]
Shirota, Matsuyuki [17 ]
Kinoshita, Kengo [17 ]
Nakamura, Yutaka [4 ]
Ohno, Isao [4 ]
Sekijima, Yoshiki [2 ]
Inokuchi, Jin-ichi [18 ]
机构
[1] Tohoku Med & Pharmaceut Univ, Inst Mol Biomembrane & Glycobiol, Div Glycopathol, Sendai, Japan
[2] Shinshu Univ, Sch Med, Dept Med Neurol & Rheumatol, Matsumoto, Japan
[3] Shinshu Univ Hosp, Ctr Med Genet, Matsumoto, Japan
[4] Tohoku Med & Pharmaceut Univ, Fac Med, Ctr Med Educ, Sendai, Japan
[5] Juntendo Univ, Fac Pharm, Lab Bioregulatory Clin Phamacol, Urayasu, Japan
[6] Juntendo Univ, Grad Sch Med, Inst Environm & Gender Specif Med, Urayasu, Japan
[7] Shinshu Univ, Sch Med, Dept Otorhinolaryngol Head & Neck Surg, Matsumoto, Japan
[8] Yokohama City Univ, Grad Sch Med, Dept Human Genet, Yokohama, Japan
[9] Yokohama City Univ Med, Dept Rare Dis Genom, Yokohama, Japan
[10] Tohoku Med & Pharmaceut Univ, Fac Med, Div Med Biochem, Sendai, Japan
[11] Tohoku Med & Pharmaceut Univ, Inst Mol Biomembrane & Glycobiol, Div Struct Glycobiol, Sendai, Japan
[12] Soka Univ, Glycan & Life Syst Integrat Ctr GaLSIC, Hachioji, Japan
[13] Nagoya Univ, Inst Glycocore Res iGCORE, Nagoya, Japan
[14] Natl Ctr Child Hlth & Dev, Dept Genome Med, Tokyo, Japan
[15] Matsumoto City Hosp, Dept Neurosurg, Matsumoto, Japan
[16] Gifu Univ, Grad Sch Med, Dept Neurol, Gifu, Japan
[17] Tohoku Univ, Tohoku Med Megabank Org, Sendai, Japan
[18] Osaka Univ, Forefront Res Ctr, Grad Sch Sci, Toyonaka, Japan
关键词
hereditary spastic paraplegia; gangliosides; B4GALNT1; GM2/GD2; synthase; glycosyltransferase; missense variant; MYELIN-ASSOCIATED GLYCOPROTEIN; EXPRESSION CLONING; COMPLEX GANGLIOSIDES; SYNTHASE; MICE; CDNA; SPECIFICITY; DEFICIENT; LIGANDS; BIOLOGY;
D O I
10.3389/fnins.2024.1437668
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 (beta-1,4-N-acetylgalactosaminyltransferase 1) 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 activation-induced 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 10 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.
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页数:12
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