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Dilated Cardiomyopathy
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Marco Merlo, Alessia Paldino, Giulia De Angelis, Gianfranco Sinagra
The genetic background of LVRR has been recently explored. Mutations in genes encoding cytoskeleton Z-disk (DES, FLNC, and DMD), obscurin-like 1 (OBSL1), nexilin F-actin binding protein (NEXN), myopalladin (MYPN), nebulette (NEBL), and LIM domain binding 3 (LDB3) have been associated with a lower rate of LVRR compared with TTN genotype in a study population of 152 DCM patients.79
Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
Familial RCMs are usually inherited in an autosomal dominant fashion. The coexistence of HCM and RCM phenotypes within the same families, and with identical disease-causing mutations, highlights the importance of modifier genes, epigenetics, and environmental influences in determining the ultimate clinical phenotype. Many of the RCM probands had pathological mutations in either β-myosin heavy chain (MYH7) or the cardiac troponin I gene (TNNI3). Mutations in other sarcomeric genes including troponin T (TTNT2), myosin-binding protein C (MYBPC3), myosin light chains (MYL 2 and 3) and α-cardiac actin (ACTC) have also been described. Hereditary forms of RCM may not typically be a distinct genetic cardiomyopathy; rather, they may represent part of the broad phenotypic spectrum of HCM that is manifested by limited (or absent) hypertrophy and restrictive physiology. Nonsarcomeric mutations have also been identified in RCM and include mutations in myopalladin (MYPN), titin (TTN) and filament-C (FLNC). FLNC is an actin cross-linking protein expressed in the heart and skeletal muscle. Cardiac myocytes show cytoplasmic inclusions suggesting protein aggregates which are specific for filament-C by immunohistochemistry. Desmin-related RCMs are very rare, characterized by intracytoplasmic accumulation of desmin and caused by mutations in the gene for desmin (DES) or alpha-beta crystallin (CRYAB). Disease expression is variable and may involve skeletal muscle alone, cardiac and skeletal muscle simultaneously or cardiac muscle alone. Conduction disease is typically present, and these mutations should be considered in young patients with RCM and atrioventricular block.
Early clinical and pre-clinical therapy development in Nemaline myopathy
Published in Expert Opinion on Therapeutic Targets, 2022
Gemma Fisher, Laurane Mackels, Theodora Markati, Anna Sarkozy, Julien Ochala, Heinz Jungbluth, Sithara Ramdas, Laurent Servais
The 12 known NM genes include NEB (nebulin), ACTA1 (alpha actin 1), TPM3 (alpha tropomyosin 3), TPM2 (beta tropomyosin or tropomyosin 2), TNNT1 (Troponin T1), KLHL40 (Kelch-like protein 40), KLHL41 (Kelch-like protein 41), CFL-2 (Cofilin 2), KBTBD13 (kelch repeat and BTB domain containing protein 13), LMOD3 (leiomodin3), MYPN (myopalladin), TNNT3 (troponin T3, fast skeletal type) [2,12,16]. These genes are summarized in Table 1 and the interaction of their protein products is depicted in Figure 1. Other genes such as MYO18B (Myosin XVIIIB) and NEFL are associated but not accepted as causative as variants in these genes are not always associated with pathological diagnosis of NM [2,31–34]. Finally, there is a proportion of patients with clinical and pathological features of NM in whom no causative gene variant/s have yet been identified [19].