Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Mary N. Sheppard in 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.
Mechanotransduction Mechanisms of Hypertrophy and Performance with Resistance Exercise
Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse in The Routledge Handbook on Biochemistry of Exercise, 2020
Exercise intensity, here defined as the percentage of a person's one-repetition maximum (1RM), directly influences the response and ultimate adaptation of skeletal muscle (Figure 6.2). Indeed, mechanotransducing pathways are thought to be minimally active following low-intensity resistance exercise (less than 50% of the 1RM), whereas high-intensity exercise (greater than 75% of the 1RM) is required for mechanotransduction. In support of this, the beta-1 integrin subunit was shown to be phosphorylated exclusively following maximal resistance exercise, whereas integrin phosphorylation remained unaffected following low-intensity exercise (66). Similarly, the steroidogenic acute regulatory protein (STAR) pathway, a key regulator of cytoskeletal turnover, also increased to a greater degree following acute resistance exercise relative to endurance exercise (93). However, while this was observed in trained subjects, untrained subjects showed no difference in STAR dynamics whether performing endurance or resistance exercise, thus demonstrating one's training status, whether novice or advanced, as a likely contributor. Moreover, a small heat shock protein integral to cytoskeletal integrity, αB-crystallin (CRYAB), was phosphorylated in an intensity-specific manner (81). Specifically, while endurance exercise increased CRYAB to a similar degree as high-intensity exercise, specifically in slow-twitch muscle fibres, CRYAB phosphorylation within fast-twitch fibres was found to be greater following high-intensity exercise. With this in mind, low-intensity exercise carried out to failure has recently shown to recruit both slow- and fast-twitch muscle fibres (121), leading to speculation as to whether maximal loads are required for heightened muscle fibre mechanotransduction. It may be that the degree to which exercise intensity influences mechanotransduction drastically differs between biophysical and biochemical mechanotransduction, with the latter being more responsive to a range of exercise intensity, whereas biophysical mechanotransduction requires a heightened stimulus for activation.
A new heterozygous mutation in the stop codon of CRYAB (p.X176Y) is liable for congenital posterior pole cataract in a Chinese family.
Published in Ophthalmic Genetics, 2021
Yinhui Yu, Jingjie Xu, Yue Qiao, Jinyu Li, Ke Yao
Interestingly, αB-crystallin is also widely expressed in several non-ocular tissues including in the cardiac and skeletal muscle (30). Mutations in the CRYAB gene can cause a variety of distinct clinical phenotypes including isolated congenital cataract, myofibrillar myopathy, cardiomyopathy, or a multisystemic disorder (16,21). The multi-systemic expression and involvement of αB-crystallin in the regulation of intracellular apoptosis in the various processes would explain the mechanism of diversity in phenotypes of CRYAB mutations.
Genetics of congenital cataract, its diagnosis and therapeutics
Published in Egyptian Journal of Basic and Applied Sciences, 2018
Luqman Khan, Nargis Shaheen, Qaisar Hanif, Shah Fahad, Muhammad Usman
The genesis of congenital cataract is still not discovered well and very little is identified because of lack of modern techniques, long-term accurate data required and the lack of intense investigative techniques. Various set of symptoms and infections prior birth suggestion to the malformations in the eye and helps in congenital cataracts development. Although various causes have been bringing into being, the particular aetiology is often difficult to determine, mostly in the patient’s sufferings from unilateral hereditary cataracts, clinically and genetically heterogeneous situation [12]. In addition, different mutations in the identical gene are able to cause similar cataract forms, in spite of the fact that the similar mutation in a distinct gene might clue to dissimilar phenotypes are indicated by variable morphologies of cataracts in few families. Isolated congenital cataracts are likely to be expressively autosomal dominant with penetrant Mendelian charismas are more common than autosomal recessive cataract. Many of these are related with additional abnormalities, mainly as a portion of developing syndromes. The key cytoplasmic proteins of human lens are encoded by mutations in different genes and are linked with cataracts of different morphologies, containing genes encoding crystallin (CRYA, CRYB, and CRYG), lens specific connexin (Cx43, Cx46, and Cx50), major intrinsic protein (MIP) or Aquaporin, paired-like homeodomain transcription factor 3 (PITX3), avian musculoaponeurotic fibrosarcoma (MAF), cytoskeletal structural proteins and heat shock transcription factor 4 (HSF4) [13]. An important concern is an αB-crystallin gene, CRYAB, which is extensively appeared in different tissues mainly in the muscle. Mutations in CRYAB can cause a range of defects ranging from isolated cataracts to minor cataracts linked with myopathy. Another example is the ferritin gene that gives rise to the hyperferritinemia-cataract syndrome [13].
Glycosylation of extracellular vesicles: current knowledge, tools and clinical perspectives
Published in Journal of Extracellular Vesicles, 2018
Charles Williams, Felix Royo, Oier Aizpurua-Olaizola, Raquel Pazos, Geert-Jan Boons, Niels-Christian Reichardt, Juan M. Falcon-Perez
Having identified glycoproteins of interest then widely used Western blot and flow cytometry techniques are appropriate for more in-depth analyses. However, whereby antibodies are the best-in-class reagents for protein recognition, their applicability to the study of glycosylation is diminished. Antibodies against N-glycans recognise families of related glycan structures as opposed to specific epitopes and monoclonal N-glycan antibodies are also exceedingly rare [73]. Indeed, in a recently compiled database of anti-glycan reagents only 25 of a total 1116 entries correspond to N-glycan antibodies [73]. In place of antibodies labelled lectins can be used in much the same manner for binding assays, though extra consideration must be given to the multimeric nature of some lectins and their weaker binding strengths. Less structurally diverse O-linked glycans and blood group antigens and more tractable towards antibody recognition and a greater repertoire of reagents is available for these. O-GlcNAc specific antibodies in particular have been used to probe the glycoproteins of EVs in colorectal cancer cell lines [74,75]. This modification is an O-linked monosaccharide addition of N-acetylglucosamine (GlcNAc) that is typically involved in nutrient sensing and cellular homeostasis but has also been implicated in cancer [76]. Through immunoblotting a heterogeneous panel of EV proteins that displayed uncharacteristically elevated O-GlcNAcylation was identified, including the significant hnRNPA2/B1 ribonucleoprotein complex responsible for loading of exosomes with miRNA [77]. Crucially, an independent study has also demonstrated that ablating O-GlcNAcylation of the cytosolic chaperone protein cryAB prevents its packaging into exosomes [78]. These findings have yet to be integrated but could reveal the presence of O-GlcNAc as another potential mechanism of glycosylation dependent cargo recruitment. Moreover, the current paradigm is that SUMOylation directs hnRNPA2/B1 recruitment [77]. There is perhaps a more complex interplay of posttranslational modifications that bears further investigation.
Related Knowledge Centers
- Crystallin
- Protein
- Gene
- Heat Shock Protein
- Tuberous Sclerosis
- Protein–Protein Interaction
- Cryaa
- Hsp27