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Stroke and Transient Ischemic Attacks of the Brain and Eye
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Along with uncommon highly penetrant mendelian mutations that may cause stroke (e.g. NOTCH 3 [19p13], α-GAL [Xq22], TREX1 [3p21], amyloid precursor protein [APP; 21q21]), several genetic loci have been associated with ischemic stroke (e.g. chromosome 12q24.12 near ALDH2) and its subtypes: the ZFHX3 gene on chromosome 16q22 and PITX2 gene on chromosome 4q25 for cardioembolic stroke, the HDAC9 gene on chromosome 7p21 and locus on chromosome 1p13.2 near the TSPAN2 gene for large-vessel stroke, and chromosome 6p25 near the FOXF2 gene for small-vessel disease.23
Regulation of the Pituitary Gland by Dopamine
Published in Nira Ben-Jonathan, Dopamine, 2020
The glycoprotein hormone alpha subunit (αGSU) is the first pituitary hormone gene expressed during embryonic development, at mouse E10.5 [43]. Thyrotrophs are derived from two different populations. The first appears in the rostral tip of the developing pituitary by E12. This population is transient and is independent of Pit1 expression. The second arises by E15.5 and is PIT1-dependent. This population corresponds to the adult thyrotrophs, indicating that Pit1 is important for transactivating TSHβ, and for maintaining the cellular lineage. Thyrotroph embryonic factor (Tef) is expressed exclusively in the rostral portion of the developing pituitary, where the thyrotrophic precursors are located. Tef transactivates the TSHβ promoter, with Pitx1 and Pitx2 also contributing to thyrotroph differentiation. In humans, the fetal thyroid gland reaches maturity by gestational week 11–12, close to the end of the first trimester and begins to secrete thyroid hormones by about gestational week 16. During this period, an adequate supply of maternal thyroid hormones must be sustained to ensure normal neurological development.
The eye
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
These are heterogeneous and at times syndromal (e.g. Rieger syndrome with mutation in PITX2, or other loci, and Peters plus syndrome with mutation in B3GALTL). They are rare and require expert diagnosis, as well as checking of the parents for minor defects. Molecular abnormalities have been found in some cases, though less consistently than in aniridia.
Precision medicine in cardiac electrophysiology: where we are and where we need to go
Published in Expert Review of Precision Medicine and Drug Development, 2020
Ashish Correa, Syed Waqas Haider, Wilbert S. Aronow
Genomic studies have now started to unravel putative genetic modulators of AF. GWAS have shown that variants in a region on chromosome 4q25 are associated with familial AF [74,75]. This region is near the PITX2 gene which suppresses sino-atrial node (SAN) gene-expression in the left atrium and thus plays an essential role in left-right differentiation in the embryonic heart. Presumably, defects in this gene permit the SAN-specific gene program in the left atrium, thereby promoting aberrant pacemaker tissue development in the left atrium and encouraging atrial arrhythmogenesis. Studies in mice models have shown precisely this, whereby PITX2 suppression resulted in AF and atrial tachycardias [76]. Interestingly, PITX2 is responsible for forming the tissue of the pulmonary vein myocardial sleeve, which has been shown to be the origin of AF in electrophysiologic mapping studies. A recent study showed that a common SNP on chromosome 4q25 significantly influenced the response to anti-arrhythmic drugs in AF patients [77]. This points to a modulatory role of genes not just in the susceptibility to AF but also the response to therapy.
MST1-Hippo pathway regulates inflammation response following myocardial infarction through inhibiting HO-1 signaling pathway
Published in Journal of Receptors and Signal Transduction, 2020
Yanan Tian, Haijiu Song, Dapeng Jin, Na Hu, Lixian Sun
ROS are essential for heart development and regeneration. The level of ROS increases in the first week after birth, and the increased ROS induce the DNA damage response of the cells in the heart that play a role in the transition from the regenerative to the nonregenerative stage. Reduced ROS level or inhibition of the DNA damage response may prolong the regenerative window of cardiomyocytes. Interestingly, a recent study reported that PITX2 interacts with YAP and induces the expression of antioxidant genes such as Ldha, Ndufb3, and Oxnad1. By performing PITX2 and YAP ChIP-seq in mouse hearts, they showed that PITX2 and YAP directly regulate the expression of these antioxidant genes. Deletion of Pitx2 in cardiomyocytes is detrimental to neonatal mouse heart regeneration [44]. However, when Pitx2 conditional knockout mice were treated with the antioxidant N-acetyl-l-cysteine, the scar size was decreased. In addition, these authors reported that NRF2, a regulator of the antioxidant response, activates PITX2 expression and also promotes PITX2 nuclear translocation [45].
Mutation Survey of Candidate Genes and Genotype–Phenotype Analysis in 20 Southeastern Chinese Patients with Axenfeld–Rieger Syndrome
Published in Current Eye Research, 2018
Xun Wang, Xing Liu, Liqin Huang, Shaohua Fang, Xiaoyun Jia, Xueshan Xiao, Shiqiang Li, Xiangming Guo
ARS is genetically heterogeneous, and approximately 40% of patients with ARS have been found to harbor mutations. The major candidate genes for ARS are PITX2 and FOXC1. PITX2 is a member of the bicoid-like homeobox transcription factor family.5 It plays a fundamental role in the genetic control of ocular anterior segment development.6,7FOXC1 is a member of the forkhead family of transcription factors. It acts as an important regulator of cell migration and differentiation during embryogenesis.8PITX2 and FOXC1 mutations are found in almost 40% of ARS patients.9 Both iris malformations and effects on the trabecular meshwork are variable in patients with ARS who have mutations in these two genes.10 A third chromosomal locus at 13q14 may also be associated with ARS.11,12 However, no candidate genes have been detected in this region. More than 50% of patients with ARS do not harbor mutations in these two genes. Recently, a whole-exome sequencing study reported that variants in the PRDM5 gene were associated with anterior segment defects, such as ARS, in a Pakistani family.13 The relationship between PRDM5 and ARS in other populations requires further study.