Abstract
TMEM151A, located at 11q13.2 and encoding transmembrane protein 151A, was recently reported as causative for autosomal dominant paroxysmal kinesigenic dyskinesia (PKD). Here, through comprehensive analysis of sporadic and familial cases, we expand the clinical and mutation spectrum of PKD. In doing so, we clarify the clinical and genetic features of Chinese PKD patients harboring TMEM151A variants and further explore the relationship between TMEM151A mutations and PKD. Whole exome sequencing was performed on 26 sporadic PKD patients and nine familial PKD pedigrees without PRRT2 variants. Quantitative real-time PCR was used to assess the gene expression of frameshift mutant TMEM151A in a PKD patient. TMEM151A variants reported to date were reviewed. Four TMEM151A variants were detected in four unrelated families with 12 individuals, including a frameshift mutation [c.606_607insA (p.Val203fs)], two missense mutations [c.166G > A (p.Gly56Arg) and c.791T > C (p.Val264Ala)], and a non-pathogenic variant [c.994G > A (p.Gly332Arg)]. The monoallelic frameshift mutation [c.606_607insA (p.Val203fs)] may cause TMEM151A mRNA decay, suggesting a potential pathogenic mechanism of haploinsufficiency. Patients with TMEM151A variants had short-duration attacks and presented with dystonia. Our study provides a detailed clinical description of PKD patients with TMEM151A mutations and reports a new disease-causing mutation, expanding the known phenotypes caused by TMEM151A mutations and providing further detail about the pathoetiology of PKD.
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Data availability
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
References
Cao L, Huang X, Wang N, Wu Z, Zhang C, Gu W, Cong S, Ma J, Wei L, Deng Y, Fang Q, Niu Q, Wang J, Wang Z, Yin Y, Tian J, Tian S, Bi H, Jiang H, Liu X, Lu Y, Sun M, Wu J, Xu E, Chen T, Chen T, Chen X, Li W, Li S, Li Q, Song X, Tang Y, Yang P, Yang Y, Zhang M, Zhang X, Zhang Y, Zhang R, Ouyang Y, Yu J, Hu Q, Ke Q, Yao Y, Zhao Z, Zhao X, Zhao G, Liang F, Cheng N, Han J, Peng R, Chen S, Tang B (2021) Recommendations for the diagnosis and treatment of paroxysmal kinesigenic dyskinesia: an expert consensus in China. Transl Neurodegener 10:7. https://doi.org/10.1186/s40035-021-00231-8
Chen WJ, Lin Y, **ong ZQ, Wei W, Ni W, Tan GH, Guo SL, He J, Chen YF, Zhang QJ, Li HF, Lin Y, Murong SX, Xu J, Wang N, Wu ZY (2011) Exome sequencing identifies truncating mutations in PRRT2 that cause paroxysmal kinesigenic dyskinesia. Nat Genet 43:1252–1255. https://doi.org/10.1038/ng.1008
Chen Y, Chen D, Zhao S, Liu G, Li H, Wu ZY (2021) Penetrance estimation of PRRT2 variants in paroxysmal kinesigenic dyskinesia and infantile convulsions. Front Med 15:877–886. https://doi.org/10.1007/s11684-021-0863-4
Chen YL, Chen DF, Li HF, Wu ZY (2022) Features differ between paroxysmal kinesigenic dyskinesia patients with PRRT2 and TMEM151A variants. Mov Disord 37:608–613. https://doi.org/10.1002/mds.28939
Ebrahimi-Fakhari D, Saffari A, Westenberger A, Klein C (2015) The evolving spectrum of PRRT2-associated paroxysmal diseases. Brain 138:3476–3495. https://doi.org/10.1093/brain/awv317
Erro R, Sheerin UM, Bhatia KP (2014) Paroxysmal dyskinesias revisited: a review of 500 genetically proven cases and a new classification. Mov Disord 29:1108–1116. https://doi.org/10.1002/mds.25933
Gardella E, Becker F, Moller RS, Schubert J, Lemke JR, Larsen LH, Eiberg H, Nothnagel M, Thiele H, Altmuller J, Syrbe S, Merkenschlager A, Bast T, Steinhoff B, Nurnberg P, Mang Y, Bakke Moller L, Gellert P, Heron SE, Dibbens LM, Weckhuysen S, Dahl HA, Biskup S, Tommerup N, Hjalgrim H, Lerche H, Beniczky S, Weber YG (2016) Benign infantile seizures and paroxysmal dyskinesia caused by an SCN8A mutation. Ann Neurol 79:428–436. https://doi.org/10.1002/ana.24580
Gardiner AR, Jaffer F, Dale RC, Labrum R, Erro R, Meyer E, **romerisiou G, Stamelou M, Walker M, Kullmann D, Warner T, Jarman P, Hanna M, Kurian MA, Bhatia KP, Houlden H (2015) The clinical and genetic heterogeneity of paroxysmal dyskinesias. Brain 138:3567–3580. https://doi.org/10.1093/brain/awv310
Heron SE, Grinton BE, Kivity S, Afawi Z, Zuberi SM, Hughes JN, Pridmore C, Hodgson BL, Iona X, Sadleir LG, Pelekanos J, Herlenius E, Goldberg-Stern H, Bassan H, Haan E, Korczyn AD, Gardner AE, Corbett MA, Gecz J, Thomas PQ, Mulley JC, Berkovic SF, Scheffer IE, Dibbens LM (2012) PRRT2 mutations cause benign familial infantile epilepsy and infantile convulsions with choreoathetosis syndrome. Am J Hum Genet 90:152–160. https://doi.org/10.1016/j.ajhg.2011.12.003
Holbrook JA, Neu-Yilik G, Hentze MW, Kulozik AE (2004) Nonsense-mediated decay approaches the clinic. Nat Genet 36:801–808. https://doi.org/10.1038/ng1403
Huang XJ, Wang SG, Guo XN, Tian WT, Zhan FX, Zhu ZY, Yin XM, Liu Q, Yin KL, Liu XR, Zhang Y, Liu ZG, Liu XL, Zheng L, Wang T, Wu L, Rong TY, Wang Y, Zhang M, Bi GH, Tang WG, Zhang C, Zhong P, Wang CY, Tang JG, Lu W, Zhang RX, Zhao GH, Li XH, Li H, Chen T, Li HY, Luo XG, Song YY, Tang HD, Luan XH, Zhou HY, Tang BS, Chen SD, Cao L (2020) The phenotypic and genetic spectrum of paroxysmal kinesigenic dyskinesia in China. Mov Disord 35:1428–1437. https://doi.org/10.1002/mds.28061
Jumper J, Evans R, Pritzel A, Green T, Figurnov M, Ronneberger O, Tunyasuvunakool K, Bates R, Zidek A, Potapenko A, Bridgland A, Meyer C, Kohl SAA, Ballard AJ, Cowie A, Romera-Paredes B, Nikolov S, Jain R, Adler J, Back T, Petersen S, Reiman D, Clancy E, Zielinski M, Steinegger M, Pacholska M, Berghammer T, Bodenstein S, Silver D, Vinyals O, Senior AW, Kavukcuoglu K, Kohli P, Hassabis D (2021) Highly accurate protein structure prediction with AlphaFold. Nature 596:583–589. https://doi.org/10.1038/s41586-021-03819-2
Khajavi M, Inoue K, Lupski JR (2006) Nonsense-mediated mRNA decay modulates clinical outcome of genetic disease. Eur J Hum Genet 14:1074–1081. https://doi.org/10.1038/sj.ejhg.5201649
Lee HY, Huang Y, Bruneau N, Roll P, Roberson ED, Hermann M, Quinn E, Maas J, Edwards R, Ashizawa T, Baykan B, Bhatia K, Bressman S, Bruno MK, Brunt ER, Caraballo R, Echenne B, Fejerman N, Frucht S, Gurnett CA, Hirsch E, Houlden H, Jankovic J, Lee WL, Lynch DR, Mohammed S, Muller U, Nespeca MP, Renner D, Rochette J, Rudolf G, Saiki S, Soong BW, Swoboda KJ, Tucker S, Wood N, Hanna M, Bowcock AM, Szepetowski P, Fu YH, Ptacek LJ (2012) Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep 1:2–12. https://doi.org/10.1016/j.celrep.2011.11.001
Li HF, Chen YL, Zhuang L, Chen DF, Ke HZ, Luo WJ, Liu GL, Wu SN, Zhou WH, **ong ZQ, Wu ZY (2021) TMEM151A variants cause paroxysmal kinesigenic dyskinesia. Cell Discov 7:83. https://doi.org/10.1038/s41421-021-00322-w
Li YL, Lv WQ, Zeng YH, Chen YK, Wang XL, Yang K, Ding YL, Chen RK, Wang N, Chen WJ (2022) Exome-wide analyses in paroxysmal kinesigenic dyskinesia confirm TMEM151A as a novel causative gene. Mov Disord 37:641–643. https://doi.org/10.1002/mds.28904
Liu X, Ke H, Qian X, Wang S, Zhan F, Li Z, Tian W, Huang X, Zhang B, Cao L (2022) Clinical and genetic analyses of 150 patients with paroxysmal kinesigenic dyskinesia. J Neurol 269:4717–4728. https://doi.org/10.1007/s00415-022-11103-0
Ma LY, Han L, Niu M, Chen L, Yu YZ, Feng T (2022) Screening of the TMEM151A gene in patients with paroxysmal kinesigenic dyskinesia and other movement disorders. Front Neurol 13:865690. https://doi.org/10.3389/fneur.2022.865690
Méneret A, Grabli D, Depienne C, Gaudebout C, Picard F, Dürr A, Lagroua I, Bouteiller D, Mignot C, Doummar D, Anheim M, Tranchant C, Burbaud P, Jedynak CP, Gras D, Steschenko D, Devos D, Billette de Villemeur T, Vidailhet M, Brice A, Roze E (2012) PRRT2 mutations: a major cause of paroxysmal kinesigenic dyskinesia in the European population. Neurology 79:170–174. https://doi.org/10.1212/WNL.0b013e31825f06c3
Méneret A, Gaudebout C, Riant F, Vidailhet M, Depienne C, Roze E (2013) PRRT2 mutations and paroxysmal disorders. Eur J Neurol 20:872–878. https://doi.org/10.1111/ene.12104
Mounir Alaoui O, Charbonneau PF, Prin P, Mongin M, Choquer M, Damier P, Riant F, Degos B (2023) TMEM151A as an alternative to PRRT2 in paroxysmal kinesigenic dyskinesia: About three new cases. Parkinsonism Relat Disord 108:105295. https://doi.org/10.1016/j.parkreldis.2023.105295
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424. https://doi.org/10.1038/gim.2015.30
Schultz J, Copley RR, Doerks T, Ponting CP, Bork P (2000) SMART: a web-based tool for the study of genetically mobile domains. Nucleic Acids Res 28:231–234. https://doi.org/10.1093/nar/28.1.231
Tian WT, Huang XJ, Mao X, Liu Q, Liu XL, Zeng S, Guo XN, Shen JY, Xu YQ, Tang HD, Yin XM, Zhang M, Tang WG, Liu XR, Tang BS, Chen SD, Cao L (2018) Proline-rich transmembrane protein 2-negative paroxysmal kinesigenic dyskinesia: clinical and genetic analyses of 163 patients. Mov Disord 33:459–467. https://doi.org/10.1002/mds.27274
Tian WT, Zhan FX, Liu ZH, Liu Z, Liu Q, Guo XN, Zhou ZW, Wang SG, Liu XR, Jiang H, Li XH, Zhao GH, Li HY, Tang JG, Bi GH, Zhong P, Yin XM, Liu TT, Ni RL, Zheng HR, Liu XL, Qian XH, Wu JY, Cao YW, Zhang C, Liu SH, Wu YY, Wang QF, Xu T, Hou WZ, Li ZY, Ke HY, Zhu ZY, Zheng L, Wang T, Rong TY, Wu L, Zhang Y, Fang K, Wang ZH, Zhang YK, Zhang M, Zhao YW, Tang BS, Luan XH, Huang XJ, Cao L (2022) TMEM151A variants cause paroxysmal kinesigenic dyskinesia: a large-sample study. Mov Disord 37:545–552. https://doi.org/10.1002/mds.28865
Tomita H, Nagamitsu S, Wakui K, Fukushima Y, Yamada K, Sadamatsu M, Masui A, Konishi T, Matsuishi T, Aihara M, Shimizu K, Hashimoto K, Mineta M, Matsushima M, Tsujita T, Saito M, Tanaka H, Tsuji S, Takagi T, Nakamura Y, Nanko S, Kato N, Nakane Y, Niikawa N (1999) Paroxysmal kinesigenic choreoathetosis locus maps to chromosome 16p11.2-q12.1. Am J Hum Genet 65:1688–1697. https://doi.org/10.1086/302682
van Vliet R, Breedveld G, de Rijk-van AJ, Brilstra E, Verbeek N, Verschuuren-Bemelmans C, Boon M, Samijn J, Diderich K, van de Laar I, Oostra B, Bonifati V, Maat-Kievit A (2012) PRRT2 phenotypes and penetrance of paroxysmal kinesigenic dyskinesia and infantile convulsions. Neurology 79:777–784. https://doi.org/10.1212/WNL.0b013e3182661fe3
Varadi M, Anyango S, Deshpande M, Nair S, Natassia C, Yordanova G, Yuan D, Stroe O, Wood G, Laydon A, Zidek A, Green T, Tunyasuvunakool K, Petersen S, Jumper J, Clancy E, Green R, Vora A, Lutfi M, Figurnov M, Cowie A, Hobbs N, Kohli P, Kleywegt G, Birney E, Hassabis D, Velankar S (2022) AlphaFold Protein Structure Database: massively expanding the structural coverage of protein-sequence space with high-accuracy models. Nucleic Acids Res 50:D439–D444. https://doi.org/10.1093/nar/gkab1061
Wang HX, Li HF, Liu GL, Wen XD, Wu ZY (2016) Mutation analysis of MR-1, SLC2A1, and CLCN1 in 28 PRRT2-negative paroxysmal kinesigenic dyskinesia patients. Chin Med J (engl) 129:1017–1021. https://doi.org/10.4103/0366-6999.180529
Wang H, Huang P, Zhu M, Fang X, Wu C, Hong D (2022) TMEM151A phenotypic spectrum includes paroxysmal kinesigenic dyskinesia with infantile convulsions. Neurol Sci 43:6095–6099. https://doi.org/10.1007/s10072-022-06208-3
Wiel L, Baakman C, Gilissen D, Veltman JA, Vriend G, Gilissen C (2019) MetaDome: pathogenicity analysis of genetic variants through aggregation of homologous human protein domains. Hum Mutat 40:1030–1038. https://doi.org/10.1002/humu.23798
Wirth T, Meneret A, Drouot N, Rudolf G, Lagha Boukbiza O, Chelly J, Tranchant C, Piton A, Roze E, Anheim M (2022) De novo mutation in TMEM151A and paroxysmal kinesigenic dyskinesia. Mov Disord 37:1115–1117. https://doi.org/10.1002/mds.29023
Yin XM, Lin JH, Cao L, Zhang TM, Zeng S, Zhang KL, Tian WT, Hu ZM, Li N, Wang JL, Guo JF, Wang RX, **a K, Zhang ZH, Yin F, Peng J, Liao WP, Yi YH, Liu JY, Yang ZX, Chen Z, Mao X, Yan XX, Jiang H, Shen L, Chen SD, Zhang LM, Tang BS (2018) Familial paroxysmal kinesigenic dyskinesia is associated with mutations in the KCNA1 gene. Hum Mol Genet 27:625–637. https://doi.org/10.1093/hmg/ddx430
Acknowledgements
We would like to acknowledge all of the patients and their families for their participation in our study.
Funding
This study was funded by the National Natural Science Foundation of China (NO.81801295 and 81501248), the Wisdom Accumulation and Talent Cultivation Project of the Third xiangya hospital of Central South University (YX202205), the Science and Technology Innovation Program of Hunan Province (2021RC3031), the Natural Foundation of **njiang Uygur Autonomous Region (No.2018D01C225), the Scientific Research Program of Hunan Provincial Health Commission (20220503347), and the Open Research Program of Key Laboratory of Regenerative Biology of Chinese Academy of Sciences (KLRB202010).
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QXZ, CYM, and DL contributed to conception and design of the study. QX Z and HL H wrote the first draft of the manuscript. HL H revised the manuscript, while QX Z and FH assisted in the preparation of the figures. FH carried out the experimental design and data analysis later. QXZ, CYM collected the clinical data. XYL, BX and GLL supervised the study. FH wrote and revised the final version of the paper. HLH, ZS and DL revised the manuscript and gave final approval of the version to be published. All authors contributed to revising the manuscript and read through and approved the submitted version.
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Huang, H.l., Zhang, Q.x., Huang, F. et al. TMEM151A variants associated with paroxysmal kinesigenic dyskinesia. Hum. Genet. 142, 1017–1028 (2023). https://doi.org/10.1007/s00439-023-02535-3
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DOI: https://doi.org/10.1007/s00439-023-02535-3