Association of TRMT2B gene variants with juvenile amyotrophic lateral sclerosis
Yanling Liu1,2, Xi He3, Yanchun Yuan4, Bin Li4,5,6, Zhen Liu4, Wanzhen Li4, Kaixuan Li2, Shuo Tan2, Quan Zhu2, Zhengyan Tang2, Feng Han2, Ziqiang Wu2, Lu Shen4,5,6,7,8,9, Hong Jiang4,5,6,7, Beisha Tang4,5,6,7, Jian Qiu5,6,7,10, Zhengmao Hu7(), Junling Wang1,4,5,6,7,8,9()
1. Department of Neurology, Xiangya Hospital, Central South University, Jiangxi, National Regional Center for Neurological Diseases, Nanchang 330038, China 2. Provincial Laboratory for Diagnosis and Treatment of Genitourinary System Disease, Department of Urology, Xiangya Hospital, Central South University, Changsha 410078, China 3. Department of Orthopedics, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310002, China 4. Department of Neurology, Xiangya Hospital, Central South University, Changsha 410078, China 5. National Clinical Research Center for Geriatric Diseases, Xiangya Hospital, Central South University, Changsha 410008, China 6. Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha 410008, China 7. Center for Medical Genetics, School of Life Sciences, Central South University, Changsha 410008, China 8. Engineering Research Center of Hunan Province in Cognitive Impairment Disorders, Central South University, Changsha 410078, China 9. Hunan International Scientific and Technological Cooperation Base of Neurodegenerative and Neurogenetic Diseases, Changsha 410078, China 10. Hunan Key Laboratory of Molecular Precision Medicine, Xiangya Hospital, Central South University, Changsha 410078, China
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive degeneration of motor neurons, and it demonstrates high clinical heterogeneity and complex genetic architecture. A variation within TRMT2B (c.1356G>T; p.K452N) was identified to be associated with ALS in a family comprising two patients with juvenile ALS (JALS). Two missense variations and one splicing variation were identified in 10 patients with ALS in a cohort with 910 patients with ALS, and three more variants were identified in a public ALS database including 3317 patients with ALS. A decreased number of mitochondria, swollen mitochondria, lower expression of ND1, decreased mitochondrial complex I activities, lower mitochondrial aerobic respiration, and a high level of ROS were observed functionally in patient-originated lymphoblastoid cell lines and TRMT2B interfering HEK293 cells. Further, TRMT2B variations overexpression cells also displayed decreased ND1. In conclusion, a novel JALS-associated gene called TRMT2B was identified, thus broadening the clinical and genetic spectrum of ALS.
Reduced CMAP, chronic neurogenic reinnervation, and ongoing denervation
Reduced CMAP, chronic neurogenic reinnervation, and ongoing denervation
Sensory
Normal
Normal
Tab.2
Sample ID
Sex
Age of onset
Gene
Chr
Position
Location
cDNA change
AA alteration
Mutation type
rsID
MAF in gnomAD
P value b
Functional predictions: pathogenic (total) c
Sequencing depth
XY003.P1 a
M
1
TRMT2B
X
100273992
Exon12
c.1356G>T
p.K452N
missense
/
/
/
2/11
79
XY003.P2 a
M
1
TRMT2B
X
100273992
Exon12
c.1356G>T
p.K452N
missense
/
/
/
2/11
86
M6783
M
66
TRMT2B
X
100296359
Exon3
c.250C>G
p.L84V
missense
rs201296426
0.0006019(119/197698)
< 0.0001
5/11
9
M7966
F
63
TRMT2B
X
100296359
Exon3
c.250C>G
p.L84V
missense
rs201296426
0.0006019(119/197698)
< 0.0001
5/11
8
S001433
F
65
TRMT2B
X
100296359
Exon3
c.250C>G
p.L84V
missense
rs201296426
0.0006019(119/197698)
< 0.0001
5/11
17
S003418
F
42
TRMT2B
X
100296359
Exon3
c.250C>G
p.L84V
missense
rs201296426
0.0006019(119/197698)
< 0.0001
5/11
11
S003943
M
50
TRMT2B
X
100296359
Exon3
c.250C>G
p.L84V
missense
rs201296426
0.0006019(119/197698)
< 0.0001
5/11
16
S004576
M
56
TRMT2B
X
100296359
Exon3
c.250C>G
p.L84V
missense
rs201296426
0.0006019(119/197698)
< 0.0001
5/11
5
S004913
M
50
TRMT2B
X
100296359
Exon3
c.250C>G
p.L84V
missense
rs201296426
0.0006019(119/197698)
< 0.0001
5/11
8
M36116
F
58
TRMT2B
X
100290675
Exon7
c.539-3T>C
/
splicing
/
/
/
39
S003640
M
65
TRMT2B
X
100274004
Exon12
c.1344T>G
p.F448L
missense
rs374183741
0.00007793(16/205319)
0.0961
6/11
61
/d
F
/
TRMT2B
X
100276156
Exon9
c.1000C>T
p.R334W
missense
rs145089500
0.00001637(3/183278)
/
6/11
/
/d
/
/
TRMT2B
X
100276212
Exon9
c.944G>T
p.R315L
missense
rs145912589
0.0001268(26/205046)
/
4/11
/
/d
/
/
TRMT2B
X
100292017
Exon5
c.484C>G
p.R162G
missense
rs141694732
0.00002923(6/205301)
/
3/11
/
Tab.3
Fig.2
Fig.3
Fig.4
Fig.5
1
MA van Es, O Hardiman, A Chio, A Al-Chalabi, RJ Pasterkamp, JH Veldink, LH van den Berg. Amyotrophic lateral sclerosis. Lancet 2017; 390(10107): 2084–2098 https://doi.org/10.1016/S0140-6736(17)31287-4
2
E Longinetti, F Fang. Epidemiology of amyotrophic lateral sclerosis: an update of recent literature. Curr Opin Neurol 2019; 32(5): 771–776 https://doi.org/10.1097/WCO.0000000000000730
3
R Chia, A Chiò, BJ Traynor. Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications. Lancet Neurol 2018; 17(1): 94–102 https://doi.org/10.1016/S1474-4422(17)30401-5
4
B Oskarsson, DK Horton, H Mitsumoto. Potential environmental factors in amyotrophic lateral sclerosis. Neurol Clin 2015; 33(4): 877–888 https://doi.org/10.1016/j.ncl.2015.07.009
L Hou, B Jiao, T Xiao, L Zhou, Z Zhou, J Du, X Yan, J Wang, B Tang, L Shen. Screening of SOD1, FUS and TARDBP genes in patients with amyotrophic lateral sclerosis in central-southern China. Sci Rep 2016; 6(1): 32478 https://doi.org/10.1038/srep32478
7
Z Liu, Y Yuan, M Wang, J Ni, W Li, L Huang, Y Hu, P Liu, X Hou, X Hou, J Du, L Weng, R Zhang, Q Niu, J Tang, H Jiang, L Shen, B Tang, J Wang. Mutation spectrum of amyotrophic lateral sclerosis in Central South China. Neurobiol Aging 2021; 107: 181–188 https://doi.org/10.1016/j.neurobiolaging.2021.06.008
JO Johnson, R Chia, DE Miller, R Li, R Kumaran, Y Abramzon, N Alahmady, AE Renton, SD Topp, JR Gibbs, MR Cookson, MS Sabir, CL Dalgard, C Troakes, AR Jones, A Shatunov, A Iacoangeli, Khleifat A Al, N Ticozzi, V Silani, C Gellera, IP Blair, C Dobson-Stone, JB Kwok, ES Bonkowski, R Palvadeau, PJ Tienari, KE Morrison, PJ Shaw, A Al-Chalabi, RH Jr Brown, A Calvo, G Mora, H Al-Saif, M Gotkine, F Leigh, IJ Chang, SJ Perlman, I Glass, AI Scott, CE Shaw, AN Basak, JE Landers, A Chiò, TO Crawford, BN Smith, BJ; FALS Sequencing Consortium; American Genome Center; International ALS Genomics Consortium; Traynor, Consortium ITALSGEN. et al.. Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis. JAMA Neurol 2021; 78(10): 1236–1248 https://doi.org/10.1001/jamaneurol.2021.2598
10
P Lanteri, I Meola, A Canosa, Marco G De, A Lomartire, MT Rinaudo, E Albamonte, VA Sansone, C Lunetta, U Manera, R Vasta, C Moglia, A Calvo, P Origone, A Chiò, P Mandich. The heterozygous deletion c.1509_1510delAG in exon 14 of FUS causes an aggressive childhood-onset ALS with cognitive impairment. Neurobiol Aging 2021; 103: 130.e1–130.e7 https://doi.org/10.1016/j.neurobiolaging.2021.01.029
11
R Sprute, H Jergas, A Ölmez, S Alawbathani, H Karasoy, HS Dafsari, K Becker, HS Daimagüler, P Nürnberg, F Muntoni, H Topaloglu, G Uyanik, S Cirak. Genotype-phenotype correlation in seven motor neuron disease families with novel ALS2 mutations. Am J Med Genet A 2021; 185(2): 344–354 https://doi.org/10.1002/ajmg.a.61951
12
YZ Chen, CL Bennett, HM Huynh, IP Blair, I Puls, J Irobi, I Dierick, A Abel, ML Kennerson, BA Rabin, GA Nicholson, M Auer-Grumbach, K Wagner, P De Jonghe, JW Griffin, KH Fischbeck, V Timmerman, DR Cornblath, PF Chance. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am J Hum Genet 2004; 74(6): 1128–1135 https://doi.org/10.1086/421054
13
A Orlacchio, C Babalini, A Borreca, C Patrono, R Massa, S Basaran, RP Munhoz, EA Rogaeva, PH St George-Hyslop, G Bernardi, T Kawarai. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain 2010; 133(2): 591–598 https://doi.org/10.1093/brain/awp325
14
A Al-Saif, F Al-Mohanna, S Bohlega. A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann Neurol 2011; 70(6): 913–919 https://doi.org/10.1002/ana.22534
15
T Altman, A Ionescu, A Ibraheem, D Priesmann, T Gradus-Pery, L Farberov, G Alexandra, N Shelestovich, R Dafinca, N Shomron, F Rage, K Talbot, ME Ward, A Dori, M Krüger, E Perlson. Axonal TDP-43 condensates drive neuromuscular junction disruption through inhibition of local synthesis of nuclear encoded mitochondrial proteins. Nat Commun 2021; 12(1): 6914 https://doi.org/10.1038/s41467-021-27221-8
16
S Anoar, NS Woodling, T Niccoli. Mitochondria dysfunction in frontotemporal dementia/amyotrophic lateral sclerosis: lessons from Drosophila models. Front Neurosci 2021; 15: 786076 https://doi.org/10.3389/fnins.2021.786076
17
F Theunissen, PK West, S Brennan, B Petrović, K Hooshmand, PA Akkari, M Keon, B Guennewig. New perspectives on cytoskeletal dysregulation and mitochondrial mislocalization in amyotrophic lateral sclerosis. Transl Neurodegener 2021; 10(1): 46 https://doi.org/10.1186/s40035-021-00272-z
T Wang, H Liu, K Itoh, S Oh, L Zhao, D Murata, H Sesaki, T Hartung, CH Na, J Wang. C9orf72 regulates energy homeostasis by stabilizing mitochondrial complex I assembly. Cell Metab 2021; 33(3): 531–546.e9 https://doi.org/10.1016/j.cmet.2021.01.005
20
A Ludolph, V Drory, O Hardiman, I Nakano, J Ravits, W Robberecht, J; WFN Research Group On ALS/MND Shefner. A revision of the El Escorial criteria—2015. Amyotrop Lat Scl Fr Deg 2015; 16(5–6): 291–292 https://doi.org/10.3109/21678421.2015.1049183
21
X Jiang, Y Teng, X Chen, N Liang, Z Li, D Liang, L Wu. Six novel mutation analysis of the androgen receptor gene in 17 Chinese patients with androgen insensitivity syndrome. Clin Chim Acta 2020; 506: 180–186 https://doi.org/10.1016/j.cca.2020.03.036
22
H Guo, P Tong, Y Liu, L Xia, T Wang, Q Tian, Y Li, Y Hu, Y Zheng, X Jin, Y Li, W Xiong, B Tang, Y Feng, J Li, Q Pan, Z Hu, K Xia. Mutations of P4HA2 encoding prolyl 4-hydroxylase 2 are associated with nonsyndromic high myopia. Genet Med 2015; 17(4): 300–306 https://doi.org/10.1038/gim.2015.28
23
Y Tian, JL Wang, W Huang, S Zeng, B Jiao, Z Liu, Z Chen, Y Li, Y Wang, HX Min, XJ Wang, Y You, RX Zhang, XY Chen, F Yi, YF Zhou, HY Long, CJ Zhou, X Hou, JP Wang, B Xie, F Liang, ZY Yang, QY Sun, EG Allen, AM Shafik, HE Kong, JF Guo, XX Yan, ZM Hu, K Xia, H Jiang, HW Xu, RH Duan, P Jin, BS Tang, L Shen. Expansion of human-specific GGC repeat in neuronal intranuclear inclusion disease-related disorders. Am J Hum Genet 2019; 105(1): 166–176 https://doi.org/10.1016/j.ajhg.2019.05.013
24
X He, Z Huang, W Liu, Y Liu, H Qian, T Lei, L Hua, Y Hu, Y Zhang, P Lei. Electrospun polycaprolactone/hydroxyapatite/ZnO films as potential biomaterials for application in bone-tendon interface repair. Coll Surf B Bioint 2021; 204: 111825 https://doi.org/10.1016/j.colsurfb.2021.111825
25
JP Grieco, SLE Compton, N Bano, L Brookover, AS Nichenko, JC Drake, EM Schmelz. Mitochondrial plasticity supports proliferative outgrowth and invasion of ovarian cancer spheroids during adhesion. Front Oncol 2023; 12: 1043670 https://doi.org/10.3389/fonc.2022.1043670
26
BR Brooks, RG Miller, M Swash, TL; World Federation of Neurology Research Group on Motor Neuron Diseases Munsat. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotrop Lat Scl Oth Mot Neur Dis 2000; 1(5): 293–299 https://doi.org/10.1080/146608200300079536
27
PA McCombe, NR Wray, RD Henderson. Extra-motor abnormalities in amyotrophic lateral sclerosis: another layer of heterogeneity. Expert Rev Neurother 2017; 17(6): 561–577 https://doi.org/10.1080/14737175.2017.1273772
28
JP Taylor. Multisystem proteinopathy: intersecting genetics in muscle, bone, and brain degeneration. Neurology 2015; 85(8): 658–660 https://doi.org/10.1212/WNL.0000000000001862
29
HL Teoh, K Carey, H Sampaio, D Mowat, T Roscioli, M Farrar. Inherited paediatric motor neuron disorders: beyond spinal muscular atrophy. Neural Plast 2017; 2017: 6509493 https://doi.org/10.1155/2017/6509493
30
M Pereira, S Francisco, AS Varanda, M Santos, MAS Santos, AR Soares. Impact of tRNA modifications and tRNA-modifying enzymes on proteostasis and human disease. Int J Mol Sci 2018; 19(12): 3738 https://doi.org/10.3390/ijms19123738
31
I Laptev, E Shvetsova, S Levitskii, M Serebryakova, M Rubtsova, A Bogdanov, P Kamenski, P Sergiev, O Dontsova. Mouse Trmt2B protein is a dual specific mitochondrial metyltransferase responsible for m5U formation in both tRNA and rRNA. RNA Biol 2020; 17(4): 441–450 https://doi.org/10.1080/15476286.2019.1694733
32
CA Powell, M Minczuk. TRMT2B is responsible for both tRNA and rRNA m5U-methylation in human mitochondria. RNA Biol 2020; 17(4): 451–462 https://doi.org/10.1080/15476286.2020.1712544
33
F Zhang, K Yoon, DY Zhang, NS Kim, GL Ming, H Song. Epitranscriptomic regulation of cortical neurogenesis via Mettl8-dependent mitochondrial tRNA m3C modification. Cell Stem Cell 2023; 30(3): 300–311.e11 https://doi.org/10.1016/j.stem.2023.01.007
34
S Sekar, J McDonald, L Cuyugan, J Aldrich, A Kurdoglu, J Adkins, G Serrano, TG Beach, DW Craig, J Valla, EM Reiman, WS Liang. Alzheimer’s disease is associated with altered expression of genes involved in immune response and mitochondrial processes in astrocytes. Neurobiol Aging 2015; 36(2): 583–591 https://doi.org/10.1016/j.neurobiolaging.2014.09.027
35
B Davarniya, H Hu, K Kahrizi, L Musante, Z Fattahi, M Hosseini, F Maqsoud, R Farajollahi, TF Wienker, HH Ropers, H Najmabadi. The role of a novel TRMT1 gene mutation and rare GRM1 gene defect in intellectual disability in two Azeri families. PLoS One 2015; 10(8): e0129631 https://doi.org/10.1371/journal.pone.0129631
36
M Igoillo-Esteve, A Genin, N Lambert, J Désir, I Pirson, B Abdulkarim, N Simonis, A Drielsma, L Marselli, P Marchetti, P Vanderhaeghen, DL Eizirik, W Wuyts, C Julier, AJ Chakera, S Ellard, AT Hattersley, M Abramowicz, M Cnop. tRNA methyltransferase homolog gene TRMT10A mutation in young onset diabetes and primary microcephaly in humans. PLoS Genet 2013; 9(10): e1003888 https://doi.org/10.1371/journal.pgen.1003888
37
G KoscielnyG YaikhomV IyerTF MeehanH Morgan J Atienza-HerreroA BlakeCK Chen R EastyA Di FenzaT FiegelM GrifithsA Horne NA KarpN KurbatovaJC MasonP MatthewsDJ Oakley A QaziJ RegnartA RethaLA SantosDJ Sneddon J WarrenH WesterbergRJ WilsonDG MelvinD Smedley SD BrownP FlicekWC SkarnesAM MallonH Parkinson. The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data. Nucleic Acids Res 2014; 42(Database issue): D802–D809 doi:10.1093/nar/gkt977
pmid: 24194600
38
KJ De Vos, AL Chapman, ME Tennant, C Manser, EL Tudor, KF Lau, J Brownlees, S Ackerley, PJ Shaw, DM McLoughlin, CE Shaw, PN Leigh, CCJ Miller, AJ Grierson. Familial amyotrophic lateral sclerosis-linked SOD1 mutants perturb fast axonal transport to reduce axonal mitochondria content. Hum Mol Genet 2007; 16(22): 2720–2728 https://doi.org/10.1093/hmg/ddm226
39
P Wang, J Deng, J Dong, J Liu, EH Bigio, M Mesulam, T Wang, L Sun, L Wang, AY Lee, WA McGee, X Chen, K Fushimi, L Zhu, JY Wu. TDP-43 induces mitochondrial damage and activates the mitochondrial unfolded protein response. PLoS Genet 2019; 15(5): e1007947 https://doi.org/10.1371/journal.pgen.1007947
40
MP Murphy. Mitochondrial dysfunction indirectly elevates ROS production by the endoplasmic reticulum. Cell Metab 2013; 18(2): 145–146 https://doi.org/10.1016/j.cmet.2013.07.006
41
F Sivandzade, S Prasad, A Bhalerao, L Cucullo. NRF2 and NF-қB interplay in cerebrovascular and neurodegenerative disorders: molecular mechanisms and possible therapeutic approaches. Redox Biol 2019; 21: 101059 https://doi.org/10.1016/j.redox.2018.11.017
