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Recessive null-allele variants in MAG associated with spastic ataxia, nystagmus, neuropathy, and dystonia

M. Zech, T. Brunet, M. Škorvánek, A. Blaschek, K. Vill, B. Hanker, I. Hüning, V. Haň, P. Došekova, Z. Gdovinová, B. Alhaddad, R. Berutti, TM. Strom, E. Růžička, EJ. Kamsteeg, JJ. van der Smagt, M. Wagner, R. Jech, J. Winkelmann

. 2020 ; 77 (-) : 70-75. [pub] 20200629

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc21026637

INTRODUCTION: The gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation. METHODS: Four unrelated patients with complex neurologic conditions underwent whole-exome sequencing within research or diagnostic settings. Following determination of the underlying genetic defects, in-depth phenotyping and literature review were performed. RESULTS: In all case subjects, we detected ultra-rare homozygous or compound heterozygous variants in MAG. The observed nonsense (c.693C > A [p.Tyr231*], c.980G > A [p.Trp327*], c.1126C > T [p.Gln376*], and 1522C > T [p.Arg508*]) and frameshift (c.517_521dupAGCTG [p.Trp174*]) alleles were predicted to result in premature termination of protein translation. Affected patients presented with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. Cerebellar signs, nystagmus, and pyramidal tract dysfunction emerged as unifying features in the majority of MAG-mutated individuals identified to date. CONCLUSIONS: Our study is the first to describe biallelic null variants in MAG, confirming that loss of myelin-associated glycoprotein causes severe infancy-onset disease with central and peripheral nervous system involvement.

Citace poskytuje Crossref.org

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$a INTRODUCTION: The gene encoding myelin-associated glycoprotein (MAG) has been implicated in autosomal-recessive spastic paraplegia type 75. To date, only four families with biallelic missense variants in MAG have been reported. The genotypic and phenotypic spectrum of MAG-associated disease awaits further elucidation. METHODS: Four unrelated patients with complex neurologic conditions underwent whole-exome sequencing within research or diagnostic settings. Following determination of the underlying genetic defects, in-depth phenotyping and literature review were performed. RESULTS: In all case subjects, we detected ultra-rare homozygous or compound heterozygous variants in MAG. The observed nonsense (c.693C > A [p.Tyr231*], c.980G > A [p.Trp327*], c.1126C > T [p.Gln376*], and 1522C > T [p.Arg508*]) and frameshift (c.517_521dupAGCTG [p.Trp174*]) alleles were predicted to result in premature termination of protein translation. Affected patients presented with variable combinations of psychomotor delay, ataxia, eye movement abnormalities, spasticity, dystonia, and neuropathic symptoms. Cerebellar signs, nystagmus, and pyramidal tract dysfunction emerged as unifying features in the majority of MAG-mutated individuals identified to date. CONCLUSIONS: Our study is the first to describe biallelic null variants in MAG, confirming that loss of myelin-associated glycoprotein causes severe infancy-onset disease with central and peripheral nervous system involvement.
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$a Brunet, Theresa $u Institute of Human Genetics, Technical University of Munich, Munich, Germany
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$a Škorvánek, Matej $u Department of Neurology, P.J. Safarik University, Kosice, Slovak Republic; Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic
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$a Blaschek, Astrid $u Dr. von Haunersches Kinderspital, Ludwig-Maximilians-Universität München, Munich, Germany
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$a Vill, Katharina $u Dr. von Haunersches Kinderspital, Ludwig-Maximilians-Universität München, Munich, Germany
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$a Hanker, Britta $u Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany
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$a Hüning, Irina $u Institute of Human Genetics, Universitätsklinikum Schleswig-Holstein, Lübeck, Germany
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$a Haň, Vladimír $u Department of Neurology, P.J. Safarik University, Kosice, Slovak Republic; Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic
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$a Došekova, Petra $u Department of Neurology, P.J. Safarik University, Kosice, Slovak Republic; Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic
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$a Gdovinová, Zuzana $u Department of Neurology, P.J. Safarik University, Kosice, Slovak Republic; Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovak Republic
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$a Alhaddad, Bader $u Institute of Human Genetics, Technical University of Munich, Munich, Germany
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$a Berutti, Riccardo $u Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technical University of Munich, Munich, Germany
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$a Strom, Tim M $u Institute of Human Genetics, Technical University of Munich, Munich, Germany
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$a Růžička, Evžen $u Department of Neurology, Charles University, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic
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$a Kamsteeg, Erik-Jan $u Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands
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$a van der Smagt, Jasper J $u Division of Laboratories, Farmacy, and Biomedical Genetics, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands
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$a Wagner, Matias $u Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technical University of Munich, Munich, Germany
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$a Jech, Robert $u Department of Neurology, Charles University, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic
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$a Winkelmann, Juliane $u Institute of Neurogenomics, Helmholtz Zentrum München, Munich, Germany; Institute of Human Genetics, Technical University of Munich, Munich, Germany; Lehrstuhl für Neurogenetik, Technische Universität München, Munich, Germany; Munich Cluster for Systems Neurology, SyNergy, Munich, Germany
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