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Cardiac Disease
Published in Vincenzo Berghella, Maternal-Fetal Evidence Based Guidelines, 2022
Preethi Pirlamarla, Gregary D. Marhefka
There are a handful of autosomal dominant cardiac conditions, for which the mother would ideally have sought prenatal screening to discuss potential transmission to children. These syndromes include hypertrophic cardiomyopathy, inherited arrhythmias like long QT, Marfan, Noonan, William, Holt-Oram, and DiGeorge (22q11 deletion) [6]. Certain genetic aortopathies are at higher risk for progressive aneurysm formation, dissection and extra-cardiac manifestations, which vary based on etiology. Genetic causes of aortopathy can contribute to intracellular pathology (ACTA2, FLNA, MYLK, PRKG1, MYH11, SKI, SMAD3,4 and TGFβR1,2) or those that affect the extracellular matrix (BGN, COL1A1, COL3A1, 5A1, FBN1, 2, LOX, MFAP5, PLOD1, PRKG1, and TGFβ1,2,3). Other genetic conditions to consider with well-known associated aortopathies are bicuspid aortic valve and Turner's syndrome (XO) [7]. As an ad-hoc member of the cardio-obstetrics team, a geneticist can assist in determining risk profiles.
Cardiac and cardiovascular disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
The genes implicated in causing aneurysms of the thoracic aorta fall into four broad categories (after Pyeritz, 2014; see Appendix 1). The principal recognised genes include the following: Structural components of the extracellular matrix (e.g. FBN1, COL3A1, COL4A5, EFEMP2)Components of the TGF or BMP signalling pathways (TGFBR1, TGFBR2, TGFB2, SMAD3)Contractile elements of vascular smooth muscle (ACTA2, MYH11, MYLK, PRKG1, PKG1, FLNA, TSC2)Components of other signalling pathways (JAG1, NOTCH1, SLCA10)
Genetic Studies of PTSD and Substance Use Disorders
Published in Anka A. Vujanovic, Sudie E. Back, Posttraumatic Stress and Substance Use Disorders, 2019
Christina M. Sheerin, Leslie A. Brick, Nicole R. Nugent, Ana B. Amstadter
With the expansion of the PGC and other large GWAS datasets, novel statistical techniques that have been developed in recent years can be applied to existing data to ask novel questions about PTSD, SUD, and their overlap (see Table 15.2 ). For example, an emerging agnostic approach known as genome-wide gene-by-environment interaction studies (GEWIS) may hold promise for understanding how genetic variation and environmental factors can interact to impact upon risk for PTSD and SUD phenotypes. Recently, in the largest GEWIS published in psychiatric genetics to date, Polimanti and colleagues (2017) demonstrated that trauma exposure interacted with a variant (rs1729578) in the PRKG1 gene in relation to alcohol misuse in African American participants in a large discovery sample, which was replicated in an independent sample, and remained significant after meta-analyzing the two separate cohorts (n = 6,744). Specifically, the minor allele was associated with greater alcohol misuse in those exposed to trauma but lower alcohol misuse among those without a trauma history. This work is important, as it represents a useful merging of the trauma and alcohol literatures and demonstrates the dynamic effect of an individual’s experience on his or her genetic constitution. Although these early findings should be interpreted with caution and need to be replicated, results suggest the importance of advanced analytic and genetic methods to be able to examine this effect to better understand how an environmental experience can impact upon a complicated outcome (e.g., alcohol misuse in the aftermath of trauma) on a molecular level (i.e., depending on an individual’s genetic risk).
The foraging gene affects alcohol sensitivity, metabolism and memory in Drosophila
Published in Journal of Neurogenetics, 2021
Anne S. Oepen, Jamie L. Catalano, Reza Azanchi, Karla R. Kaun
Taken together, the work here contributes to a mechanistic understanding of alcohol sensitivity as indication for AUD by demonstrating how natural variation in metabolic phenotypes can impact behavioral response to an addictive substance. Our data predict that variants of for with lower PKG activity in other species will show increased ethanol sensitivity, and increased lasting ethanol preference. This is consistent with results on the role of PKG in ethanol-induced behaviors from rodent models, suggesting the effects of PKG on alcohol behaviors are highly conserved. cGMP-dependent protein kinase type II (cGKII) knockout mice showed elevated alcohol preference in a 2-bottle free choice test (Werner et al., 2004), demonstrating that reduction in PKG is associated with increased alcohol preference in both mice and flies. Moreover, cGMP activates nitric oxide, which inhibits dopamine release in the striatum in rats resulting in decreasing reward response for alcohol (Guevara-Guzman et al., 1994; Romieu et al., 2008). These studies are consistent with rovers showing decreased ethanol preference, as they have higher PKG activity than sitters. Whether this is the mechanism through which variation in PRKG1 increases risk for alcohol abuse in humans remains to be seen (Hawn et al., 2018; Polimanti et al., 2018).
Formin proteins in megakaryocytes and platelets: regulation of actin and microtubule dynamics
Published in Platelets, 2019
Malou Zuidscherwoude, Hannah L.H. Green, Steven G. Thomas
DIAP1 (also known as DIAPH1, but commonly known as mDia1) is the most studied formin and was found as an effector of the small GTPase RhoA in the formation of actin stress fibres (13). In its active form, it is a potent actin nucleator and accelerates filament elongation. mDia1 is activated as described above by GTP bound Rho GTPase binding to the GBD causing displacement of the DAD domain from the N terminal region of mDia1. However, other members of the formin protein family show different mechanisms of DAD release; for example, DAAM1 is activated when the PDZ domain of the Dishevelled (Dvl) protein binds to the DAD domain rather than by Rho binding (14). Similarly, although FHOD1 is recruited to the plasma membrane by active Rac1 binding, this formin seems not to be activated by GTPase interactions. Instead the auto-inhibitory state is disturbed by the phosphorylation of residues in its DAD domain by Rho effector kinase ROCK (15) and cGMP-dependent protein kinase 1 (PRKG1) (16).