Congenital Titinopathies Linked to Mutations in TTN Metatranscript-Only Exons.

Autor: Perrin A; Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, 34093 Montpellier, France.; PhyMedExp, INSERM, CNRS, Université de Montpellier, 34093 Montpellier, France., Garcia-Uzquiano R; AP-HP, GHU Université Paris-Saclay, Neuromuscular Center, Child Neurology and ICU Department, Raymond Poincare Hospital, 92380 Garches, France., Stojkovic T; AP-HP, Centre de Référence des Maladies Neuromusculaires Nord/Est/Île-de-France, Sorbonne Université, Hôpital Pitié-Salpêtrière, 75013 Paris, France., Tard C; Département de Neurologie et des Troubles du Mouvement, U1172, Centre Hospitalo Universitaire (CHU) de Lille, CT, Centre de Référence des Maladies Neuromusculaires Nord/Est/Île-de-France, 59000 Lille, France., Metay C; AP-HP, UF Molecular Cardiogenetics and Myogenetics, Sorbonne Université and Sorbonne Université UPMC Paris 06, Inserm UMRS974, Research Center in Myology, Pitié-Salpêtrière Hospital, 75013 Paris, France., Bergougnoux A; Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, 34093 Montpellier, France.; PhyMedExp, INSERM, CNRS, Université de Montpellier, 34093 Montpellier, France., Van Goethem C; Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, 34093 Montpellier, France., Thèze C; Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, 34093 Montpellier, France., Larrieux M; Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, 34093 Montpellier, France., Faure-Gautron H; Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, 34093 Montpellier, France.; PhyMedExp, INSERM, CNRS, Université de Montpellier, 34093 Montpellier, France., Laporte J; Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Inserm U1258, CNRS UMR 7104, Université de Strasbourg, 67400 Illkirch, France., Lefebvre G; Service d'Imagerie Musculo-Squelettique, CCIAL, CHU de Lille, Rue Emile Laine, 59037 Lille, France., Krahn M; INSERM, Marseille Medical Genetics, U1251, Aix-Marseille Université, 13385 Marseille, France.; Département de Génétique Médicale, Hôpital Timone Enfants, APHM, 13385 Marseille, France., Juntas-Morales R; Neurology Department, Vall d'Hebron University Hospital, 08035 Barcelona, Spain., Titin's Network Collaborators, Koenig M; Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, 34093 Montpellier, France.; PhyMedExp, INSERM, CNRS, Université de Montpellier, 34093 Montpellier, France., Quijano-Roy S; AP-HP, GHU Université Paris-Saclay, Neuromuscular Center, Child Neurology and ICU Department, Raymond Poincare Hospital, 92380 Garches, France.; U1179 INSERM-UVSQ, Université de Versailles, 78180 Montigny, France., Carlier RY; U1179 INSERM-UVSQ, Université de Versailles, 78180 Montigny, France.; AP-HP, GHU Université Paris-Saclay, DMU Smart Imaging, Radiology Department, Raymond Poincaré Teaching Hospital, 92380 Garches, France., Cossée M; Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, 34093 Montpellier, France.; PhyMedExp, INSERM, CNRS, Université de Montpellier, 34093 Montpellier, France.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2024 Dec 03; Vol. 25 (23). Date of Electronic Publication: 2024 Dec 03.
DOI: 10.3390/ijms252312994
Abstrakt: Congenital titinopathies reported to date show autosomal recessive inheritance and are caused by a variety of genomic variants, most of them located in metatranscript (MTT)-only exons. The aim of this study was to describe additional patients and establish robust genotype-phenotype associations in titinopathies. This study involved analyzing molecular, clinical, pathological, and muscle imaging features in 20 patients who had at least one pathogenic or likely pathogenic TTN variant in MTT-only exons, with onset occurring antenatally or in the early postnatal stages. The 20 patients with recessive inheritance exhibited a heterogeneous range of phenotypes. These included fetal lethality, progressive weakness, cardiac or respiratory complications, hyper-CKemia, or dystrophic muscle biopsies. MRI revealed variable abnormalities in different muscles. All patients presented severe congenital myopathy at birth, characterized by arthrogryposis (either multiplex or axial-distal) or neonatal hypotonia in most cases. This study provides detailed genotype-phenotype correlations in congenital titinopathies caused by mutations in MTT-only exons. The findings highlight the variability in clinical presentation and the severity of phenotypes associated with these specific genetic alterations. RNA-seq analyses provided valuable insights into the molecular consequences of TTN variants, particularly in relation to splicing defects and nonsense-mediated RNA decay. In conclusion, this study reinforces the genotype-phenotype correlations between congenital myopathies and variants in TTN MTT-only exons, improves their molecular diagnosis, and provides a better understanding of their pathophysiology.
Databáze: MEDLINE
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