TY - JOUR
T1 - Making sense of missense variants in TTN-related congenital myopathies
AU - Rees, Martin
AU - Nikoopour, Roksana
AU - Fukuzawa, Atsushi
AU - Kho, Ay Lin
AU - Fernandez-Garcia, Miguel
AU - Wraige, Elizabeth
AU - Bodi, Istvan
AU - Deshpande, Charu
AU - Özdemir, Özkan
AU - Daimagüler, Hülya-Sevcan
AU - Pfuhl, Mark
AU - Holt, Mark
AU - Brandmeier, Birgit
AU - Grover, Sarah
AU - Longman, Cheryl
AU - Farrugia, Maria Elena
AU - Fluss, Joël
AU - Matthews, Emma
AU - Hanna, Michael
AU - Muntoni, Francesco
AU - Sarkozy, Anna
AU - Phadke, Rahul
AU - Quinlivan, Rosaline
AU - Oates, Emily
AU - Schröder, Rolf
AU - Thiel, Christian
AU - Reimann, Jens
AU - Voermans, Nicol
AU - Erasmus, Corrie
AU - Kamsteeg, Erik-Jan
AU - Konersman, Chaminda
AU - Grosmann, Carla
AU - Mckee, Shane
AU - Tirupathi, Sandya
AU - Moore, Steven A
AU - Wilichowski, Ekkehard
AU - Hobbiebrunken, Elke
AU - Dekomien, Gabriele
AU - Richard, Isabelle
AU - van den Bergh, Peter
AU - Domínguez-González, Cristina
AU - Cirak, Sebahattin
AU - Ferreiro, Ana
AU - Jungbluth, Heinz
AU - Gautel, Mathias
PY - 2020/12/20
Y1 - 2020/12/20
N2 - 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. TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of 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.
AB - 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. TTN-related myopathies show considerable overlap with other myopathies but are strongly suggested by a combination of 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.
M3 - Article
SN - 0001-6322
JO - Acta Neuropathologica
JF - Acta Neuropathologica
ER -