Pathogenic deep intronic MTM1 variant activates a pseudo-exon encoding a nonsense codon resulting in severe X-linked myotubular myopathy.

Autor: Bryen SJ; Kids Neuroscience Centre, Kids Research Institute, The Children's Hospital at Westmead, Westmead, NSW, Australia.; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia., Oates EC; Kids Neuroscience Centre, Kids Research Institute, The Children's Hospital at Westmead, Westmead, NSW, Australia.; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia., Evesson FJ; Kids Neuroscience Centre, Kids Research Institute, The Children's Hospital at Westmead, Westmead, NSW, Australia.; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia.; Functional Neuromics, Children's Medical Research Institute, Westmead, NSW, Australia., Lu JK; Kids Neuroscience Centre, Kids Research Institute, The Children's Hospital at Westmead, Westmead, NSW, Australia.; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia., Waddell LB; Kids Neuroscience Centre, Kids Research Institute, The Children's Hospital at Westmead, Westmead, NSW, Australia.; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia., Joshi H; Kids Neuroscience Centre, Kids Research Institute, The Children's Hospital at Westmead, Westmead, NSW, Australia., Ryan MM; Department of Neurology, Royal Children's Hospital, Parkville, VIC, Australia.; Neurosciences Research, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia.; Department of Paediatrics, University of Melbourne, Parkville, VIC, Australia., Cummings BB; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; Medical and Population Genetics, Broad Institute of Harvard & MIT, Boston, MA, USA.; Center for Mendelian Genomics, Broad Institute of Harvard & MIT, Boston, MA, USA., McLean CA; Anatomical Pathology, Alfred Hospital, Prahran, VIC, Australia., MacArthur DG; Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA.; Medical and Population Genetics, Broad Institute of Harvard & MIT, Boston, MA, USA.; Center for Mendelian Genomics, Broad Institute of Harvard & MIT, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA., Kornberg AJ; Department of Neurology, Royal Children's Hospital, Parkville, VIC, Australia.; Neurosciences Research, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, VIC, Australia., Cooper ST; Kids Neuroscience Centre, Kids Research Institute, The Children's Hospital at Westmead, Westmead, NSW, Australia. sandra.cooper@sydney.edu.au.; Discipline of Child and Adolescent Health, Faculty of Medicine and Health, The University of Sydney, Westmead, NSW, Australia. sandra.cooper@sydney.edu.au.; Functional Neuromics, Children's Medical Research Institute, Westmead, NSW, Australia. sandra.cooper@sydney.edu.au.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2021 Jan; Vol. 29 (1), pp. 61-66. Date of Electronic Publication: 2020 Aug 29.
DOI: 10.1038/s41431-020-00715-7
Abstrakt: X-linked myotubular myopathy (XLMTM) is a severe congenital myopathy characterised by generalised weakness and respiratory insufficiency. XLMTM is associated with pathogenic variants in MTM1; a gene encoding the lipid phosphatase myotubularin. Whole genome sequencing (WGS) of an exome-negative male proband with severe hypotonia, respiratory insufficiency and centralised nuclei on muscle biopsy identified a deep intronic MTM1 variant NG_008199.1(NM_000252.2):c.1468-577A>G, which strengthened a cryptic 5' splice site (A>G substitution at the +5 position). Muscle RNA sequencing was non-diagnostic due to low read depth. Reverse transcription PCR (RT-PCR) of muscle RNA confirmed the c.1468-577A>G variant activates inclusion of a pseudo-exon encoding a premature stop codon into all detected MTM1 transcripts. Western blot analysis establishes deficiency of myotubularin protein, consistent with the severe XLMTM phenotype. We expand the genotypic spectrum of XLMTM and highlight benefits of screening non-coding regions of MTM1 in male probands with phenotypically concordant XLMTM who remain undiagnosed following exome sequencing.
Databáze: MEDLINE
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