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Making sense of missense variants in TTN-related congenital myopathies.


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.

SUBMITTER: Rees M 

PROVIDER: S-EPMC7882473 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Making sense of missense variants in TTN-related congenital myopathies.

Rees Martin M   Nikoopour Roksana R   Fukuzawa Atsushi A   Kho Ay Lin AL   Fernandez-Garcia Miguel A MA   Wraige Elizabeth E   Bodi Istvan I   Deshpande Charu C   Özdemir Özkan Ö   Daimagüler Hülya-Sevcan HS   Pfuhl Mark M   Holt Mark M   Brandmeier Birgit B   Grover Sarah S   Fluss Joël J   Longman Cheryl C   Farrugia Maria Elena ME   Matthews Emma E   Hanna Michael M   Muntoni Francesco F   Sarkozy Anna A   Phadke Rahul R   Quinlivan Ros R   Oates Emily C EC   Schröder Rolf R   Thiel Christian C   Reimann Jens J   Voermans Nicol N   Erasmus Corrie C   Kamsteeg Erik-Jan EJ   Konersman Chaminda C   Grosmann Carla C   McKee Shane S   Tirupathi Sandya S   Moore Steven A SA   Wilichowski Ekkehard E   Hobbiebrunken Elke E   Dekomien Gabriele G   Richard Isabelle I   Van den Bergh Peter P   Domínguez-González Cristina C   Cirak Sebahattin S   Ferreiro Ana A   Jungbluth Heinz H   Gautel Mathias M  

Acta neuropathologica 20210115 3


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 identifi  ...[more]

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