Rees, Martin, Nikoopour, Roksana, Fukuzawa, Atsushi, Kho, Ay Lin, Fernandez-Garcia, Miguel A., Wraige, Elizabeth, Bodi, Istvan, Deshpande, Charu, Oezdemir, Oezkan, Daimagueler, Hulya-Sevcan, Pfuhl, Mark, Holt, Mark, Brandmeier, Birgit, Grover, Sarah, Fluss, Joel, Longman, Cheryl, Farrugia, Maria Elena, Matthews, Emma ORCID: 0000-0002-3810-306X, Hanna, Michael ORCID: 0000-0003-0825-4075, Muntoni, Francesco, Sarkozy, Anna, Phadke, Rahul, Quinlivan, Ros, Oates, Emily C., Schroeder, Rolf, Thiel, Christian, Reimann, Jens ORCID: 0000-0003-3349-6877, Voermans, Nicol, Erasmus, Corrie, Kamsteeg, Erik-Jan, Konersman, Chaminda, Grosmann, Carla, McKee, Shane, Tirupathi, Sandya, Moore, Steven A., Wilichowski, Ekkehard, Hobbiebrunken, Elke, Dekomien, Gabriele, Richard, Isabelle, Van den Bergh, Peter, Dominguez-Gonzalez, Cristina, Cirak, Sebahattin, Ferreiro, Ana, Jungbluth, Heinz and Gautel, Mathias (2021). Making sense of missense variants in TTN-related congenital myopathies. Acta Neuropathol., 141 (3). S. 431 - 454. NEW YORK: SPRINGER. ISSN 1432-0533

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Abstract

Mutations in the sarcomeric protein titin, encoded by TTN, are emerging as a common cause of myopathies. The diagnosis of a TTN-related myopathy is, however, often not straightforward due to clinico-pathological overlap with other myopathies and the prevalence of TTN variants in control populations. Here, we present a combined clinico-pathological, genetic and biophysical approach to the diagnosis of TTN-related myopathies and the pathogenicity ascertainment of TTN missense variants. We identified 30 patients with a primary TTN-related congenital myopathy (CM) and two truncating variants, or one truncating and one missense TTN variant, or homozygous for one TTN missense variant. We found that TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of certain clinico-pathological features. Presentation was typically at birth with the clinical course characterized by variable progression of weakness, contractures, scoliosis and respiratory symptoms but sparing of extraocular muscles. Cardiac involvement depended on the variant position. Our biophysical analyses demonstrated that missense mutations associated with CMs are strongly destabilizing and exert their effect when expressed on a truncating background or in homozygosity. We hypothesise that destabilizing TTN missense mutations phenocopy truncating variants and are a key pathogenic feature of recessive titinopathies that might be amenable to therapeutic intervention.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Rees, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nikoopour, RoksanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fukuzawa, AtsushiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kho, Ay LinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fernandez-Garcia, Miguel A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wraige, ElizabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bodi, IstvanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Deshpande, CharuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oezdemir, OezkanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Daimagueler, Hulya-SevcanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pfuhl, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Holt, MarkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brandmeier, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grover, SarahUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fluss, JoelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Longman, CherylUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Farrugia, Maria ElenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Matthews, EmmaUNSPECIFIEDorcid.org/0000-0002-3810-306XUNSPECIFIED
Hanna, MichaelUNSPECIFIEDorcid.org/0000-0003-0825-4075UNSPECIFIED
Muntoni, FrancescoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sarkozy, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Phadke, RahulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Quinlivan, RosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oates, Emily C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeder, RolfUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiel, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reimann, JensUNSPECIFIEDorcid.org/0000-0003-3349-6877UNSPECIFIED
Voermans, NicolUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Erasmus, CorrieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kamsteeg, Erik-JanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Konersman, ChamindaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grosmann, CarlaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
McKee, ShaneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tirupathi, SandyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moore, Steven A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wilichowski, EkkehardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hobbiebrunken, ElkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dekomien, GabrieleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Richard, IsabelleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Van den Bergh, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dominguez-Gonzalez, CristinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cirak, SebahattinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ferreiro, AnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jungbluth, HeinzUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gautel, MathiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-607417
DOI: 10.1007/s00401-020-02257-0
Journal or Publication Title: Acta Neuropathol.
Volume: 141
Number: 3
Page Range: S. 431 - 454
Date: 2021
Publisher: SPRINGER
Place of Publication: NEW YORK
ISSN: 1432-0533
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
Clinical Neurology; Neurosciences; PathologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/60741

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