Exon skip-inducing variants in FLNA in an attenuated form of frontometaphyseal dysplasia.

Pathogenic variation in the X-linked gene FLNA causes a wide range of human developmental phenotypes. Loss-of-function is usually male embryonic-lethal, and most commonly results in a neuronal migration disorder in affected females. Gain-of-function variants cause a spectrum of skeletal dysplasias that present with variable additional, often distinctive, soft-tissue anomalies in males and females. Here we present two, unrelated, male individuals with novel, intronic variants in FLNA that are predicted to be pathogenic. Their phenotypes are reminiscent of the gain-of-function spectrum without the skeletal manifestations. Most strikingly, they manifest urethral anomalies, cardiac malformations, and keloid scarring, all commonly encountered features of frontometaphyseal dysplasia. Both variants prevent inclusion of exon 40 into the FLNA transcript, predicting the in-frame deletion of 42 amino acids, however the abundance of FLNA protein was equivalent to that observed in healthy individuals. Loss of these 42 amino acids removes sites that mediate key FLNA functions, including binding of some ligands and phosphorylation. This phenotype further expands the spectrum of the FLNA filaminopathies.

Distribution and function of the muscarinic receptor subtypes in the cardiovascular system.

Muscarinic acetylcholine receptors belong to the G protein-coupled receptor superfamily and are widely known to mediate numerous functions within the central and peripheral nervous system. Thus, they have become attractive therapeutic targets for various disorders. It has long been known that the parasympathetic system, governed by acetylcholine, plays an essential role in regulating cardiovascular function. Unfortunately, due to the lack of pharmacologic selectivity for any one muscarinic receptor, there was a minimal understanding of their distribution and function within this region. However, in recent years, advancements in research have led to the generation of knockout animal models, better antibodies, and more selective ligands enabling a more thorough understanding of the unique role muscarinic receptors play in the cardiovascular system. These advances have shown muscarinic receptor 2 is no longer the only functional subtype found within the heart and muscarinic receptors 1 and 3 mediate both dilation and constriction in the vasculature. Although muscarinic receptors 4 and 5 are still not well characterized in the cardiovascular system, the recent generation of knockout animal models will hopefully generate a better understanding of their function. This mini review aims to summarize recent findings and advances of muscarinic involvement in the cardiovascular system.

Identification and development of a subtype-selective allosteric AKT inhibitor suitable for clinical development.

The serine/threonine protein kinase AKT plays a pivotal role within the PI3K pathway in regulating cellular proliferation and apoptotic cellular functions, and AKT hyper-activation via gene amplification and/or mutation has been implicated in multiple human malignancies. There are 3 AKT isoenzymes (AKT1-3) which mediate critical, non-redundant functions. We present the discovery and development of ALM301, a novel, allosteric, sub-type selective inhibitor of AKT1/2. ALM301 binds in an allosteric pocket created by the combined movement of the PH domain and the catalytic domain, resulting in a DFG out conformation. ALM301 was shown to be highly selective against a panel of over 450 kinases and potently inhibited cellular proliferation. These effects were particularly pronounced in MCF-7 cells containing a PI3KCA mutation. Subsequent cellular downstream pathway analysis in this sensitive cell line revealed potent inhibition of pAKT signalling up to 48 h post dosing. ALM301 treatment was well tolerated in an MCF-7 xenograft model and led to a dose-dependent reduction in tumour growth. Enhanced efficacy was observed in combination with tamoxifen. In summary, ALM301 is a highly specific AKT 1/2 inhibitor with an excellent pharmacological profile suitable for further clinical development.