Novel Recessive TNNT1 Congenital Core-Rod Myopathy in French Canadians
| Autor: | Rebecca Robertson, Jason Karamchandani, Xavier Allard-Chamard, Marc Petitclerc, Benjamin Ellezam, Vandana Gupta, Denis Brunet, Nicolas Chrestian, Emily C Troiano, Bernard Brais, Marie-Josée Dicaire, Chamindra G. Konersman, Alan H. Beggs, David Pellerin, Jodi Warman Chardon, Asli Aykanat, Jean Mathieu |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Pathology medicine.medical_specialty Myopathies Nemaline Rhabdomyolysis Article Morpholinos 03 medical and health sciences 0302 clinical medicine Nemaline myopathy Troponin T medicine Missense mutation Animals Humans RNA Messenger Myopathy Child Muscle Skeletal Zebrafish Muscle contracture Muscle biopsy medicine.diagnostic_test business.industry Skeletal muscle Middle Aged medicine.disease Congenital myopathy Magnetic Resonance Imaging 030104 developmental biology medicine.anatomical_structure Neurology Gene Knockdown Techniques Female Neurology (clinical) medicine.symptom business 030217 neurology & neurosurgery |
| Zdroj: | Ann Neurol |
| ISSN: | 1531-8249 |
| Popis: | Objective Recessive null variants of the slow skeletal muscle troponin T1 (TNNT1) gene are a rare cause of nemaline myopathy that is fatal in infancy due to respiratory insufficiency. Muscle biopsy shows rods and fiber type disproportion. We report on 4 French Canadians with a novel form of recessive congenital TNNT1 core-rod myopathy. Methods Patients underwent full clinical characterization, lower limb magnetic resonance imaging (MRI), muscle biopsy, and genetic testing. A zebrafish loss-of-function model using morpholinos was created to assess the pathogenicity of the identified variant. Wild-type or mutated human TNNT1 mRNAs were coinjected with morpholinos to assess their abilities to rescue the morphant phenotype. Results Three adults and 1 child shared a novel missense homozygous variant in the TNNT1 gene (NM_003283.6: c.287T > C; p.Leu96Pro). They developed from childhood very slowly progressive limb-girdle weakness with rigid spine and disabling contractures. They suffered from restrictive lung disease requiring noninvasive mechanical ventilation in 3 patients, as well as recurrent episodes of rhabdomyolysis triggered by infections, which were relieved by dantrolene in 1 patient. Older patients remained ambulatory into their 60s. MRI of the leg muscles showed fibrofatty infiltration predominating in the posterior thigh and the deep posterior leg compartments. Muscle biopsies showed multiminicores and lobulated fibers, rods in half the patients, and no fiber type disproportion. Wild-type TNNT1 mRNA rescued the zebrafish morphants, but mutant transcripts failed to do so. Interpretation This study expands the phenotypic spectrum of TNNT1 myopathy and provides functional evidence for the pathogenicity of the newly identified missense mutation. ANN NEUROL 2020;87:568-583. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text