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Disorders of bone and connective tissue
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Limb reduction defects may be extremely difficult to distinguish from each other. Some, in particular asymmetrical amputation defects associated with ‘amniotic constriction bands’, are likely to be non-genetic. Other asymmetrical defects may be associated with oesophageal, anal, cardiac, renal and vertebral abnormalities (the VATER or VACTERL association); again, the recurrence risk is low. Thalidomide was previously a major cause, but no other definite drug-induced defects of this type are known. The severe symmetrical limb reduction disorder Roberts syndrome, which shows a characteristic abnormality of chromosomal division, is autosomal recessive. Limb changes in Holt-Oram syndrome (autosomal dominant mutations in TBX5) can be very similar to those caused by thalidomide and may occur without accompanying cardiac defect.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Genetics: autosomal dominant, almost complete penetrance; mutations in the gene TBX5 can be found in roughly 70% of patients; in a few cases mutations in the gene SALL4 have been identified. TBX5 is a member of the T-box family of transcription factors and is involved in specification of cardiac and forelimb structures during embryogenesis. TBX5 interacts with NKX2.5 and GATA4 in regulating cardiogenesis, particularly in cardiac septation, and is involved in the development of the cardiac conduction system. SALL4 encodes the sal-like protein 4, which contains 3 C2H2 double zinc finger domains of the SAL-type. Sal-like protein 4 is essential for the development of the epiblast and primitive endoderm from the inner embryonic cell mass. It interacts with SALL1 in anorectal, heart, brain and renal development and with TBX5 in patterning and morphogenesis of the first digit of the upper limbs. Other conditions caused by mutations in SALL4 are Duane radial ray syndrome and acro-renal-ocular syndrome (AROS).
Congenital and Developmental Abnormalities
Published in Harry Griffiths, Musculoskeletal Radiology, 2008
This is an autosomal dominant syndrome first described in 1960 and has an incidence of 1 in 100,000 births. However, most cases are due to spontaneous mutation in the gene that codes for transcription factor TBX5, located on the long arm of chromosome 12. This results in abnormalities of the upper extremity and in cardiac abnormalities. Upper extremity involvement is always present and results in aplasia or hypoplasia of the radial, carpal, or thenar bones. In approximately three-quarters of the patients, associated cardiac deformities are also present, most commonly an atrial or ventricular septal defect.
A comprehensive review of cardiotoxic effects of selected plants
Published in Toxin Reviews, 2021
Akbar Anaeigoudari, Nahid Azdaki, Mohammad Reza Khazdair
Li et al. (2019) also investigated the effects of paeoniflorin (the main chemical ingredient in herbaceous peony) against carditoxicity effects of aconitine on h9c2 cells. The results indicated a significant increase in cell proliferation, Bcl-2/Bax ratio, up-regulation of p53 level, reduction of caspase 3 and decrement of intracellular malondialdehyde (MDA) and extracellular lactate dehydrogenase (LDH) in paeoniflorin treated group compared to aconitine group. While there was not any significant difference in intracellular superoxide dismutase (SOD) between two groups (Li et al.2019). It has been reported that aconitine (2.5 μg/L) caused a deficient cardiovascular system with yolk sac hemorrhage and early cardiac dysfunctions in embryonic zebrafish. It also decreased the expression of cardiac genes such as, Tbx5, Gata4, and Nkx2.5 in the early stage of embryo (Liu et al.2019).
Congenital extremity anomalies with a TBX5 pathogenic variant in consecutive IVF assisted pregnancies: a case report of Holt-Oram Syndrome
Published in Journal of Obstetrics and Gynaecology, 2022
Omar Sobh, Robert O’Sullivan, Maurice J. Mahoney, Gary Kleinman
Holt-Oram Syndrome is caused by haploinsufficiency of the TBX5 gene. This gene encodes for a transcription factor, T-box 5, which activates genes involved in the development of the upper limbs, cardiac septum, and cardiac conduction system (Basson et al. 1997; Gros and Tabin 2014). TBX5 is a transcription factor that promotes cardiomyocyte differentiation by associating with NKX2-5 (Hiroi et al. 2001). In approximately 26% of cases, molecular analysis does not identify a variant in TBX5. This may suggest variation in the noncoding or regulatory regions associated with TBX5 or genetic heterogeneity that is not yet recognised (McDermott et al. 2005).
Induced pluripotent stem cell derived cardiac models: effects of Thymosin β4
Published in Expert Opinion on Biological Therapy, 2018
Tilman Ziegler, Rabea Hinkel, Christian Kupatt
While cardiomyocytes generated from iPSCs display the key features of cardiomyocytes, they remain relatively immature. On the one hand, iPSC-derived cardiomyocytes (iPSC-CMs) express cardiac contractile proteins (TNNT2, MYH6, ACTN2, MYL7, MYL2) that are organized into a sarcomeric structure and show the capability to contract [10]. However, while a primitive cardiomyocyte phenotype might be achieved by the differentiation of iPSCs, full maturation into adult cardiomyocytes so far has not been accomplished. This fact is highlighted by the small size of iPSC-derived cardiomyocytes in comparison to adult cardiomyocytes expressing fetal isoforms of contractile proteins (e.g. cardiac troponin) as well as a fetal-like cellular distribution of gap junction proteins N-cadherin and connexin 43 [48–50]. Furthermore, recapitulating embryonic development, iPSC-derived cardiomyocytes differentiate into three classes of cardiomyocytes, namely atrial, ventricular and AV-node cells [10]. These three cell types are mainly distinguishable by the action potentials they generate, with atrial cardiomyocytes showing the shortest action potential and ventricular cardiomyocytes a longer plateau phase [51]. Multiple attempts have been made to enhance the cardiomyocyte phenotype of iPSC-CMs via changes to the microenvironment or the addition of hormones or growth factors. In early stages of differentiation a treatment with the growth factors activin A, BMP4, VEGF-A, and bFGF resulted in a drastic increase of a KDRlow/C-KITneg. population of progenitors positive for ISL and TBX5 which could subsequently be further differentiated into endothelial cells (by addition of bFGF) or cardiomyocytes (by treatment with DKK1 and downregulation of Wnt) [52]. At later stages of differentiation, a treatment with the thyroid hormone triiodothyronine was able to reduce cell cycle activity of iPSCs during differentiation as well as increase cell size and sarcomere length while only the addition of dexamethasone was able to induce the development of a substantial t-tubule network necessary for a proper electromechanical coupling of cardiomyocytes [53,54]. Both mechanical and electrical stimulation has further enhanced the maturation of iPSC-CMs, with the combination of both in particular enhancing stress fiber formation and sarcomeric length shortening as well as reducing transmembrane calcium currents [55]. Furthermore, coculturing embryoid bodies together with visceral endodermal-like cells [56] or the creation of specific microenvironments such as cellular molds forcing cells into elongated shapes have demonstrated to produce more mature iPSC-CMs [57].