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High-grade Glioma
Published in David A. Walker, Giorgio Perilongo, Roger E. Taylor, Ian F. Pollack, Brain and Spinal Tumors of Childhood, 2020
Donald C. Macarthur, Christof M. Kramm, Matthias A. Karajannis
There is a striking anatomic predilection for particular driver mutations in pediatric HGG, which points to neurodevelopmental origins of pediatric HGG. Histone H3.3 G34R or G34V mutations are predominantly found in supratentorial hemispheric tumors that can vary considerably in histological appearance, which does not appear to impact on outcome.27 Histone H3 K27M mutations are found in midline tumors, including the thalamus and brainstem, with the highest frequency in DIPG).9,10,28–30 In midline tumors, FGFR1 mutations are found in thalamic HGGs while ACVR1 mutations are restricted to DIPG. DIPGs are also characterized by PIK3CA and PIK3R1 mutations and FGF1R and MET amplifications, while loss of CDKN2A and NF1 aberrations are more prevalent in supratentorial HGG.
TGF-β signaling in testicular development, spermatogenesis, and infertility
Published in Rajender Singh, Molecular Signaling in Spermatogenesis and Male Infertility, 2019
Poonam Mehta, Meghali Joshi, Rajender Singh
Inhibin-α deficiency is associated with testicular tumors, because inhibin and FSH levels are inversely related and FSH regulates the gonadal cell proliferation (89). Recently, transcriptome analysis studies in seminomas and of TCam-2 seminoma model cell line revealed the potentially active pathways. Combined datasets from Affymetrix microarrays and RNAseq analysis revealed the presence of transcript levels of TGF-β signaling. GDF3, GDF11 and BMP7 transcripts were consistently detected in seminomas and TCam-2. Transcripts encoding receptor proteins such as ACVR1A and ACVR1B, ACVR2A and ACVR2B were also detected at high levels (90).
Metabolic and endocrine bone disorders
Published in Ashley W. Blom, David Warwick, Michael R. Whitehouse, Apley and Solomon’s System of Orthopaedics and Trauma, 2017
Like bone resorption, bone formation is regulated by a combination of systemic and locally produced factors acting to promote osteoblast differentiation. Arguably the most important local factors in regulating osteoblast differentiation are the bone morphogenetic proteins (BMPs) and the Wnt signalling system, both of which comprise complex systems of multiple ligands, cell surface receptors, intracellular signalling pathways and endogenous inhibitors. Recognition of the role of these systems in bone formation has helped in understanding rare bone diseases characterized by excessive bone formation For example, activating mutations of the BMP receptor Activin A receptor type I (ACVR1) causes the bone disease fibrous ossificons progressiva, which is associated with progressive transformation of muscle into bone. BMPs are produced commercially to enhance local osteogenesis, for example to treat non-union of fractures or fuse bones (Rihn et al., 2008).
Longitudinal study of the activities of daily living and quality of life in Japanese patients with fibrodysplasia ossificans progressiva
Published in Disability and Rehabilitation, 2019
Yasuo Nakahara, Hiroshi Kitoh, Yasuharu Nakashima, Junya Toguchida, Nobuhiko Haga
Fibrodysplasia ossificans progressiva (FOP; OMIM 135100) occurs because of a heterozygous mutation in the activin A receptor, type 1 (ACVR1) gene, a type of bone morphogenetic protein receptor. This rare congenital disease causes heterotopic ossification of muscle tissue and the surrounding membranes, tendons, and ligaments throughout the body, thus leading to systemic ankyloses [1]. Linkage analysis of 32 cases of sporadic FOP and five families with heritable FOP revealed a common mutation (617 G > A) in the ACVR1 gene in sporadic and heritable cases. Other atypical variants of FOP (atypical FOP) have been identified, and 11 point mutation sites have been identified on the ACVR1 gene [1–14].
Druggable targets, clinical trial design and proposed pharmacological management in fibrodysplasia ossificans progressiva
Published in Expert Opinion on Orphan Drugs, 2020
Robert J. Pignolo, Frederick S. Kaplan
Missense mutations in the gene for ACVR1/ALK2 encoding Activin A receptor type I/Activin-like kinase 2, a bone morphogenetic protein (BMP) type I receptor are responsible for all known cases of FOP [8,9]. A heterozygous mutation (c.617 G > A; p.R206 H) in the glycine-serine (GS) activation domain of ACVR1/ALK2 accounts for about 97% of cases. Other mutations in ACVR1/ALK2 have been described in patients with variant clinical features of FOP [8,10–17]. Substitutions of conserved amino acids serve to activate the ACVR1 protein and enhance receptor signaling. Some genotype-phenotype correlations have been reported on the basis of age of onset or congenital skeletal abnormalities [8].
Induced degradation of protein kinases by bifunctional small molecules: a next-generation strategy
Published in Expert Opinion on Drug Discovery, 2019
Though rare, the heterozygous mutation (R206H) in a type I (ligand-activated) bone morphogenetic protein (BMP) receptor kinase (ACVR1/ALK2; activin receptor-like kinase 2; receptor protein serine/threonine kinase, EC 2.7.11.30) is linked to a severe musculoskeletal disorder (FOP; Fibrodysplasia Ossificans Progressiva; OMIM 135100) causes metamorphosis of soft tissues into extra-skeletal or heterotopic bone, restricting mobility throughout the body in a stepwise, cumulative manner. At present, at least six pharmaceutical companies (BioCryst, Blueprint, Clementia/Ipsen, Keros, La Jolla, Regeneron) have made efforts to develop a therapeutic for FOP, which cannot currently be effectively managed much less prevented or even diminished in frequency or extent. All but two are developing ATP-competitive, selective inhibitors of ALK2 receptor kinase. Regeneron has entered phase 1 clinical trials with a monoclonal antibody that neutralizes the non-canonical ligand (activin) with a specific neofunction of activating the R206H mutant but not wildtype ALK2 receptor kinase in the heterozygous FOP patients. Clementia/Ipsen has ushered a retinoic acid receptor-γ agonist (orphan drug designation, initially developed by Roche), palovarotene, through ongoing phase 2 and phase 3 trials, that broadly dampens BMP signaling by reducing SMAD1/5/8 phosphorylation [78]. Unfortunately, palovarotene showed severely adverse effects on skeletal maturation in a mouse model, perhaps due to the dampening of all BMP signaling and/or the chronic administration required to retard or restrain HO [79]. Interestingly, proteasome-mediated degradation of the phosphorylated downstream effectors is the proposed mechanism of action, based on the promotion of degradation of phosphorylated SMAD1 by all-trans-retinoic acid [80].