De Novo ATP1A1 Variants in an Early-Onset Complex Neurodevelopmental Syndrome

被引:6
作者
Dohrn, Maike F. [1 ,2 ,3 ]
Rebelo, Adriana P. [1 ,2 ]
Srivastava, Siddharth [4 ]
Cappuccio, Gerarda [5 ,6 ]
Smigiel, Robert [7 ]
Malhotra, Alka [8 ]
Basel, Donald [9 ]
van de Laar, Ingrid [10 ]
Neuteboom, Rinze Frederik [11 ]
Aarts-Tesselaar, Coranne [12 ]
Mahida, Sonal [4 ]
Brunetti-Pierri, Nicola [5 ,6 ]
Taft, Ryan J. [8 ]
Zuchner, Stephan [1 ,2 ]
机构
[1] Univ Miami, Miller Sch Med, Dr John T Macdonald Fdn, Dept Human Genet, Coral Gables, FL 33124 USA
[2] Univ Miami, Miller Sch Med, John P Hussman Inst Human Gen, Coral Gables, FL 33124 USA
[3] RWTH Aachen Univ Hosp, Fac Med, Dept Neurol, Aachen, Germany
[4] Harvard Med Sch, Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA
[5] Univ Naples Federico II, Dept Translat Med, Naples, Italy
[6] Telethon Inst Genet & Med, Naples, Italy
[7] Wroclaw Med Univ, Dept Pediat & Rare Disorders, Wroclaw, Poland
[8] Illumina Inc, San Diego, CA USA
[9] Med Coll Wisconsin, Dept Genet, Div Pediat Genet, Milwaukee, WI 53226 USA
[10] Erasmus MC, Univ Med Ctr Rotterdam, Dept Clin Genet, Rotterdam, Netherlands
[11] Eramus MC, Med Ctr Rotterdam, Dept Neurol, Rotterdam, Netherlands
[12] Amphia Hosp, Breda, Netherlands
关键词
MUTATIONS;
D O I
10.1212/WNL.0000000000013276
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
ATP1A1 encodes the alpha 1 subunit of the sodium-potassium ATPase, an electrogenic cation pump highly expressed in the nervous system. Pathogenic variants in other subunits of the same ATPase, encoded by ATP1A2 or ATP1A3, are associated with syndromes such as hemiplegic migraine, dystonia, or cerebellar ataxia. Worldwide, only 16 families have been reported carrying pathogenic ATP1A1 variants to date. Associated phenotypes are axonal neuropathies, spastic paraplegia, and hypomagnesemia with seizures and intellectual disability. By whole exome or genome sequencing, we identified 5 heterozygous ATP1A1 variants, c.674A>G;p.Gln225Arg, c.1003G>T;p.Gly335Cys, c.1526G>A;p.Gly509Asp, c.2152G>A;p.Gly718Ser, and c.2768T>A;p.Phe923Tyr, in 5 unrelated children with intellectual disability, spasticity, and peripheral, motor predominant neuropathy. Additional features were sensory loss, sleep disturbances, and seizures. All variants occurred de novo and are absent from control populations (MAF GnomAD = 0). Affecting conserved amino acid residues and constrained regions, all variants have high pathogenicity in silico prediction scores. In HEK cells transfected with ouabain-insensitive ATP1A1 constructs, cell viability was significantly decreased in mutants after 72h treatment with the ATPase inhibitor ouabain, demonstrating loss of ATPase function. Replicating the haploinsufficiency mechanism of disease with a gene-specific assay provides pathogenicity information and increases certainty in variant interpretation. This study further expands the genotype-phenotype spectrum of ATP1A1.
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收藏
页码:440 / 445
页数:6
相关论文
共 6 条
[1]   A map of constrained coding regions in the human genome [J].
Havrilla, James M. ;
Pedersen, Brent S. ;
Layer, Ryan M. ;
Quinlan, Aaron R. .
NATURE GENETICS, 2019, 51 (01) :88-+
[2]   ATP1A1 mutations cause intermediate Charcot-Marie-Tooth disease [J].
He, Jin ;
Guo, Lingling ;
Lin, Shan ;
Chen, Wenfeng ;
Xu, Guorong ;
Cai, Bin ;
Xu, Liuqing ;
Hong, Jingmei ;
Qiu, Liangliang ;
Wang, Ning ;
Chen, Wanjin .
HUMAN MUTATION, 2019, 40 (12) :2334-2343
[3]   Mutations in ATP1A1 Cause Dominant Charcot-Marie-Tooth Type 2 [J].
Lassuthova, Petra ;
Rebelo, Adriana P. ;
Ravenscroft, Gianina ;
Lamont, Phillipa J. ;
Davis, Mark R. ;
Manganelli, Fiore ;
Feely, Shawna M. ;
Bacon, Chelsea ;
Brozkova, Dana Safka ;
Haberlova, Jana ;
Mazanec, Radim ;
Tao, Feifei ;
Saghira, Cima ;
Abreu, Lisa ;
Courel, Steve ;
Powell, Eric ;
Buglo, Elena ;
Bis, Dana M. ;
Baxter, Megan F. ;
Ong, Royston W. ;
Marns, Lorna ;
Lee, Yi-Chung ;
Bai, Yunhong ;
Isom, Daniel G. ;
Barro-Soria, Rene ;
Chung, Ki W. ;
Scherer, Steven S. ;
Larsson, H. Peter ;
Laing, Nigel G. ;
Choi, Byung-Ok ;
Seeman, Pavel ;
Shy, Michael E. ;
Santoro, Lucio ;
Zuchner, Stephan .
AMERICAN JOURNAL OF HUMAN GENETICS, 2018, 102 (03) :505-514
[4]   ATP1A1 de novo Mutation-Related Disorders: Clinical and Genetic Features [J].
Lin, Zehong ;
Li, Jinliang ;
Ji, Taoyun ;
Wu, Ye ;
Gao, Kai ;
Jiang, Yuwu .
FRONTIERS IN PEDIATRICS, 2021, 9
[5]   Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability [J].
Schlingmann, Karl P. ;
Bandulik, Sascha ;
Mammen, Cherry ;
Tarailo-Graovac, Maja ;
Holm, Rikke ;
Baumann, Matthias ;
Koenig, Jens ;
Lee, Jessica J. Y. ;
Drogemoller, Britt ;
Imminger, Katrin ;
Beck, Bodo B. ;
Altmueller, Janine ;
Thiele, Holger ;
Waldegger, Siegfried ;
van't Hoff, William ;
Kleta, Robert ;
Warth, Richard ;
van Karnebeek, Clara D. M. ;
Vilsen, Bente ;
Bockenhauer, Detlef ;
Konrad, Martin .
AMERICAN JOURNAL OF HUMAN GENETICS, 2018, 103 (05) :808-816
[6]   Hereditary spastic paraplegia is a novel phenotype for germline de novo ATP1A1 mutation [J].
Stregapede, Fabrizia ;
Travaglini, Lorena ;
Rebelo, Adriana P. ;
Cintra, Vivian Pedigone ;
Bellacchio, Emanuele ;
Bosco, Luca ;
Alfieri, Paolo ;
Pro, Stefano ;
Zuchner, Stephan ;
Bertini, Enrico ;
Nicita, Francesco .
CLINICAL GENETICS, 2020, 97 (03) :521-526