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Identification of Genes Underlying Polygenic Obesity in Animal Models
Published in Claude Bouchard, The Genetics of Obesity, 2020
Craig H. Warden, Janis S. Fisler
Young C57BL/6J mice and FI hybrids (M. spretus × C57BL/6J) have about 13% body fat, whereas young M. spretus are very lean. Obesity is first observed in the backcross mice, where body fat varies from less than 1 % to greater than 50% of wet carcass weight. The simplest model for this observation is that obesity results from the interactions of two genes and that one locus must be homozygous for C57BL/6J alleles (BB) while the other locus is heterozygous (SB), since this is the only combination of two genes which is unique to backcross mice. It is possible that there are actually three or more genes involved in this obesity, with two or more genes for either homozygous BB or heterozygous SB type of loci. Thus, backcross obesity may be an example of a heterozygous epistasis interaction between two or more genes. This is a mechanism which might be of considerable importance in outbred populations such as humans, where both heterozygosity and homozygosity are common. It has been demonstrated experimentally that obesity genes help animals survive prolonged fasts; that is, there may be evolutionary selection favoring mice heterozygous for obesity genes.49
Carnitine transporter deficiency
Published in William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop, Atlas of Inherited Metabolic Diseases, 2020
William L. Nyhan, Georg F. Hoffmann, Aida I. Al-Aqeel, Bruce A. Barshop
The nature of the defect has been demonstrated by study of the uptake of carnitine in vitro by cultured fibroblasts (see Figure 35.3) [1, 3]. In control cells, the uptake of 14C-labeled carnitine was via a high-affinity, carrier-mediated transport process with an apparent Km of 3.24 ± 0.5 and a Vmax of 1.67 ± 0.19 [1] consistent with previous reports [23]. Fibroblasts from patients have shown little uptake of carnitine; at a concentration of carnitine of 5 mmol/L, control uptake was 0.94 and a patient uptake was 0.1 pmol/min per mg protein [1]. High-affinity transport is best shown at lower concentrations; up to 1 mmol/L uptake was negligible. Uptake in patients at high concentrations, such as 10 or 20 mmol/L reflect a second low-affinity transporter [22] or passive diffusion [24]. Transport of carnitine in control fibroblasts is sodium-dependent [1]. The uptake of carnitine by fibroblasts at 5 mmol/L showed no overlap among patients and controls. The velocity of carnitine uptake can be measured in lymphoblasts, as well as fibroblasts [25]. Patients display rates below 10 percent of control. Heterozygosity can be demonstrated in some patients by rates below 40 percent of control. Low uptake of carnitine has also been demonstrated in cultured myocytes derived from patients [26]. Prenatal diagnosis has been accomplished by demonstration of defective uptake of carnitine from amniocytes of an affected fetus [27].
The Iodotyrosine Deiodinase Defect
Published in Geraldo Medeiros-Neto, John Bruton Stanbury, Inherited Disorders of the Thyroid System, 2019
Geraldo Medeiros-Neto, John Bruton Stanbury
Demonstration of heterozygosity has depended generally on finding that at a given load of carrier DIT a larger than normal fraction of the labeled DIT was deiodinated. Fletcher et al.51 found that little of a 150-mg dose of 1-ΜΓΓ given intravenously appeared in the urine undeiodinated, but with increasing amounts of carrier iodine a progressively smaller amount of the tracer appeared unchanged in the urine. For purposes of identifying heterozygotes they proposed 25 to 50 mg of stable DIT along with the labeled DIT as an amount of carrier that would saturate the deiodinating system and provide a deiodinating rate that would indicate the deiodinating capacity of the system, and accordingly separate normal subjects from homo- and heterozygotes.
Personalizing tamoxifen therapy in adjuvant therapy: a brief summary of the ongoing discussion
Published in Expert Review of Clinical Pharmacology, 2023
Anabel Sanchez-Spitman, Henk-Jan Guchelaar
In 2014, the International Tamoxifen Pharmacogenomics Consortium carried out a meta-analysis as an attempt to give a definitive answer to this topic [16]. In this study, 4973 breast cancer patients who received adjuvant endocrine therapy with tamoxifen were studied by testing three predefined inclusion criteria. Of the three analysis, only in the most limited and restricted criterion a significantly poorer survival result in PM was observed (HR: 1.25, 95% CI: 1.06–1.47, p-value: 0.009). While for many researchers this meta-analysis was accepted as a conclusive proof of the association between improved clinical outcomes and the role of CYP2D6 polymorphisms in breast cancer patients treated with tamoxifen, many other authors have been highly critical with these conclusions. An important and relevant limitation was the exclusion of studies such as ATAC [17], TEAM [18] or BIG1-98 [19], mainly due to loss of heterozygosity as observed in these studies. In theory, patients might be categorized in the ‘incorrect’ predicted phenotype due to the loss of heterozygosity. However, a meta-analysis by Ahern et al. evaluated the clinical relevance of the loss of heterozygosity in tamoxifen-treated patients [20]. Authors concluded that, despite the strong arguments for the relevance of loss of heterozygosity, it might lack clinical relevance. In any case, since this putative association between tamoxifen efficacy, CYP2D6 genotyping, and clinical outcomes still remains unclear, many other approaches have been suggested as alternatives for potentially guiding tamoxifen efficacy.
Hb Alessandria [β37(C3)Trp→Leu; HBB: c.113G>T]: a Novel Variant on the β-Globin Chain with Slightly Increased Affinity for Oxygen Detected by Capillary Electrophoresis
Published in Hemoglobin, 2022
Lara Calcagno, Maria M. Ciriello, Monica Maccarini, Massimo Mogni, Massimo Maffei, Giuseppina Barberio, Sauro Maoggi, Domenico Coviello, Giovanni Ivaldi
Structural variants of hemoglobin (Hb) account for approximately 75.0% of all known Hb variations. In most cases, they are produced by point mutations on globin genes and substitution of an amino acid on one of the globin chains with very heterogeneous effects [1]. The physicochemical characteristics of Hb variants are reflected in the phenotypes produced and depend on the type of chain mutated and the position of the substitution, as well as the characteristics of the amino acids involved. In addition, several important phenotypic changes can be observed when an amino acid substitution alters the contacts between globin chains, the contact with heme, or the contact with oxygen. It is also necessary to consider when a mutation is on only one allele (heterozygous condition), on both alleles (homozygous condition), or is present in compound heterozygosity or in association with other defects. Each of these conditions will be equally decisive in many cases in defining the clinical phenotype.
Very early prenatal diagnosis of Cockayne’s syndrome by coelocentesis
Published in Journal of Obstetrics and Gynaecology, 2022
Antonino Giambona, Margherita Vinciguerra, Filippo Leto, Filippo Cassarà, Gaspare Cucinella, Valentina Cigna, Emanuela Orlandi, Maria Piccione, Francesco Picciotto, Aurelio Maggio
This family was a not related couple with a previous affected daughter. At the age of 3 months, the girl had bilateral cataracts, her head circumference did not increase, she tended to lose weight weighing at 2 year 7 kg. She died when she was four years old. After the death of the child, the woman became pregnant and underwent CVS for CS. She had no reliable results and she underwent amniocentesis. At 22 weeks, an unaffected foetus was diagnosed. This family came from Apulia to our diagnostic centre. The 29 year old woman and her partner were carrier of the same deletion of two nucleotides in the exon 6 (c.1431_1432delGA (p.K478Tfs*9)) which involved the ERCC6/CSB gene (NM_00123.4) (Figure 5). This defect was reported as disease causing mutation (ClinVar, HGMD, Calmels 2018). Coelocentesis was performed at 8+0 weeks of gestation and 1100 µL of CF was aspired. No maternal DNA contamination was found and no abnormal ultrasound signs were evident (Figure 5). DNA analysis showed the presence of mutation in heterozygosity. The patient refused to undergo the control by amniocentesis and molecular analysis at birth confirmed the result of the prenatal diagnosis (Table 2).