Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy

Justine Géraud (1) , Klaus Dieterich (2, 3) , John Rendu (4) , Emmanuelle Uro Coste (3) , Murielle Dobrzynski (5) , Pascale Marcorelle (6) , Christine Ioos (7) , Norma Beatriz Romero (8) , Eloise Baudou (1) , Julie Brocard (4) , Anne-Cécile Coville (1) , Julien Fauré (4) , Michel Koenig (9, 10) , Raul Juntas Morales (9, 10, 11) , Emmanuelle Lacène (8) , Angéline Madelaine (8) , Isabelle Marty (4) , Henri Pegeot (9, 10) , Corinne Theze (9, 10) , Aurore Siegfried (4) , Mireille Cossee (9, 10) , Claude Cances (1)

1 Neurologie générale et maladies inflammatoires du système nerveux [Toulouse]
2 GIN - [GIN] Grenoble Institut des Neurosciences
3 CRCT - Centre de Recherches en Cancérologie de Toulouse
4 GIN - Groupe d'imagerie neurofonctionnelle
5 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
6 CHU - BREST - Biologie pathologie - CHRU Brest, Pôle de Biologie Pathologie
7 Hôpital Raymond Poincaré [AP-HP]
8 Institut de Myologie
9 LGMR - Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques
10 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
11 INM - Institut des Neurosciences de Montpellier

Background : Congenital nemaline myopathies are rare pathologies characterised by muscle weakness and rod-shaped inclusions in the muscle fibres. Methods : Using next-generation sequencing, we identified three patients with pathogenic variants in the Troponin T type 1 (TNNT1) gene, coding for the troponin T (TNT) skeletal muscle isoform. Results : The clinical phenotype was similar in all patients, associating hypotonia, orthopaedic deformities and progressive chronic respiratory failure, leading to early death. The anatomopathological phenotype was characterised by a disproportion in the muscle fibre size, endomysial fibrosis and nemaline rods. Molecular analyses of TNNT1 revealed a homozygous deletion of exons 8 and 9 in patient 1; a heterozygous nonsense mutation in exon 9 and retention of part of intron 4 in muscle transcripts in patient 2; and a homozygous, very early nonsense mutation in patient 3.Western blot analyses confirmed the absence of the TNT protein resulting from these mutations. Discussion : The clinical and anatomopathological presentations of our patients reinforce the homogeneous character of the phenotype associated with recessive TNNT1 mutations. Previous studies revealed an impact of recessive variants on the tropomyosin-binding affinity of TNT. We report in our patients a complete loss of TNT protein due to open reading frame disruption or to post-translational degradation of TNT.

Domaines: Sciences du Vivant [q-bio]

Justine Géraud, Klaus Dieterich, John Rendu, Emmanuelle Uro Coste, Murielle Dobrzynski, et al.. Clinical phenotype and loss of the slow skeletal muscle troponin T in three new patients with recessive TNNT1 nemaline myopathy. Journal of Medical Genetics, 2020, ⟨10.1136/jmedgenet-2019-106714⟩. ⟨hal-02964560⟩