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Aneuploidy in Human Oocytes and Preimplantation Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
The first genome-wide association study (GWAS) to identify common variants that affect aneuploidy in preimplantation embryos has been conducted. Using aneuploidy data from around 46,000 embryos (a mix of day 3 and day 5) from 4700 individuals, McCoy and colleagues found no association with putative maternal meiotic origin and maternal genotypes at the statistical significance threshold used. However, they found that a 600 Kb region (quantitative trait loci, QTL) of low recombination on chromosome 4 that was associated with multiple, complex aneuploidies of mitotic origin (they followed paternal chromosomes, since the meiotic error rate is very low in sperm). The QTL contained common variants of PLK4, a polo-like kinase that regulates centrosome numbers and whose dysregulation can lead to large-scale chromosome missegregation (122,123). Importantly, it was the maternal PLK4 variants that influenced mitotic chromosome segregation, consistent with the model that maternal factors drive the initial mitotic divisions in human preimplantation embryos (58,124,125). Although the QTL contains seven other gene variants, PLK4 is an attractive candidate since it regulates centriole duplication, a critical part of the centrosome cycle, and also mediates spindle formation during the initial cell divisions in mouse and bovine embryos (122,123). Thus, PLK4 variants may cause tripolar spindle formation that results in chaotic karyotypes (Figure 8.11). Importantly, tripolar spindles originating from normally fertilized human embryos have been observed (118).
The Role of Biology in the Courtroom
Published in Gail S. Anderson, Biological Influences on Criminal Behavior, 2019
In two other Dutch cases, the court considered that pedophilia was genetic. In one, the defense counsel argued that his client’s sexual orientation, which resulted in his addiction to child pornography, was not under his control, so he should not be considered criminally responsible. The court did not accept these arguments, stating that the defendant may not be able to control his pedophilic orientation but he could control his pedophilic activities, such as collecting and distributing child pornography and assaulting a child.6 In a more unusual genetic case in the Netherlands, Huntington’s disease, the result of a single gene variant on chromosome 4, was used as both an aggravating and a mitigating factor. The accused was convicted of arson after he attempted to burn down his girlfriend’s house, endangering her life and several others’. Huntington’s disease is a progressive disease that causes dementia and an inability to deal with problems and can possibly result in impulsive aggression. He was found not criminally responsible for the crime (mitigating) but was confined to a psychiatric institution indefinitely to prevent recidivism, due to the expected progression of the disease (aggravating).6
Pet and Huntington’s Disease
Published in W. R. Wayne Martin, Functional Imaging in Movement Disorders, 2019
Huntington’s disease is a fatal, hyperkinetic movement disorder characterized by chorea, dementia, and psychiatric symptoms.12 The disease is inherited in an autosomal dominant fashion and the defective gene has been localized to the short arm of chromosome 4 through the use of molecular biological approaches.3,4 The age of onset varies widely, but typically occurs during the third and fourth decades of life.
Ophthalmological Manifestations of Hereditary Myopathies
Published in Journal of Binocular Vision and Ocular Motility, 2022
Marta Saint-Gerons, Miguel Angel Rubio, Gemma Aznar, Ana Matheu
FSHD1 is an autosomal dominant disorder caused by a deletion of a variable number of tandem D4Z4 repeats located in chromosome 4. FSHD2 form is caused by mutations, in the SMCHD1 gene, the chromatin regulator, or in the DNMT3B gene.75,76 The median age of onset is 29–32 years, but it can begin in infancy or later in adulthood.77,78 Facioscapulohumeral muscular dystrophy (FSHD) is characterized by progressive muscle weakness with the involvement of the face, scapula, upper arms, tibial and axial muscles. Extra muscular involvement may occur and include sensorineural hearing loss, and rarely, cognitive impairment or seizures. Vascular anomalies have been described and include microaneurysm, tortuosity of arterial retinal vessels, foveal hypoplasia, telangiectasias, vascular anomalies in the retinal periphery that mimics Coats disease, and electroretinogram alterations.79 Other ophthalmological findings are ptosis, lagophthalmos, and reduced intraocular pressure.80,81
State-of-the-art pharmacological approaches to reduce chorea in Huntington’s disease
Published in Expert Opinion on Pharmacotherapy, 2021
Jessie S. Gibson, Daniel O. Claassen
Huntington’s disease (HD) is an autosomal dominant, neurodegenerative disease caused by an expansion of CAG trinucleotide repeats on chromosome 4. HD is characterized by abnormal involuntary movements, cognitive decline, and behavior changes. Chorea is the most prominent symptom of HD, and average onset is in the 4th or 5th decade of life. In 1872, George Huntington published an early description of chorea as an irregular, spasmodic dance-like movement that, in HD, progresses to every voluntary muscle in the body [1]. In the following years, the disease was called ‘Huntington’s chorea’, and not for another century did ‘Huntington’s disease’ become more-widely used, acknowledging that HD is typified by more than chorea alone. Even so, chorea remains a focal component of modern HD treatment and investigation. In fact, participation in most HD clinical trials hinges on a diagnosis of ‘motor-manifest’ HD. In the years since HD was first described, a number of advances have been made. Most notable was the isolation of the HD gene in 1993. Since that time, breakthroughs have come in the form of pharmacological treatments to reduce chorea. Here we aim to describe HD chorea and approaches for management, as well as promising directions in HD research.
Vitamin D-binding protein as a biomarker to confirm specific clinical diagnoses
Published in Expert Review of Molecular Diagnostics, 2020
Barbara Lisowska-Myjak, Aleksandra Jóźwiak-Kisielewska, Jacek Łukaszkiewicz, Ewa Skarżyńska
Vitamin D-binding protein (DBP) also known as Gc-globulin is a plasma glycoprotein with a molecular weight of 56–58 kDa composed of 458 amino acids and first identified by Hirschfeld in 1959. In humans, it is encoded by the Gc gene localized to chromosome 4 (4q11-q13) and its length is 1690 nucleotides. DBP is highly polymorphic with three commonly recognized variants (Gc1F, Gc1S, and Gc2) and over 120 rare variants. The DBP–encoding gene is part of a gene cluster (the albumin multigene family) that includes albumin, alpha-fetoprotein and afamin, exhibiting amino acid sequence homology. DBP is primarily synthesized by hepatic parenchymal cells and expressed in several tissues, including the liver, kidney, gonads, fat, and neutrophils. The DBP molecule contains two longer domains (I and II) and a shorter, C-terminal domain (III) which differ in specificity and localization of various ligand-binding sites [1–5].