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The Genetic Risk of a Couple Aiming to Conceive
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Joe Leigh Simpson, Svetlana Rechitsky, Anver Kuliev
DNA-based screening actually began in the 1990s as the Human Genome Initiative was under development, albeit on a more limited basis than at present. Screening for carriers of Tay-Sachs disease was initially based solely on protein gene product, hexosaminidase A. However, only a few base mutations are responsible for most cases of Tay-Sachs in the Ashkenazim. Screening these mutations resulted in high heterozygote carrier frequencies. Other autosomal recessive disorders in the Ashkenazim could similarly be screened for. Carrier screening was thus recommended by ACOG for Canavan disease and for familial dysautonomia (25), with “consideration” given for other disorders common in the Ashkenazim: mucolipidosis IV; Niemann-Pick disease type A; Fanconi anemia types A, B, C; Bloom syndrome; Gaucher disease (GBA); Joubert syndrome; familial hyperinsulinemia (ABCC8); maple syrup urine integrated (BCKDHA, BCKDHB, DBT) disease; and Usher syndrome. In addition to Canavan disease and familial dysautonomia, ACMG recommended screening for Niemann-Pick (type A) and Bloom syndrome. DNA panels for these disorders detect 95–99% of heterozygotes. The same approach was later applied in pan-ethnic couples carrying other mutant genes.
Maple syrup urine disease (branched-chain oxoaciduria)
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
A founder effect and mutational hot-spot mutation has been reported c.11/del C in Portuguese gypsies in whom MSUD is common [68]. A patient detected by newborn screening was found to be developing normally and passed rigorous psychometric assessment despite the presence of the characteristic biochemical phenotype, including alloisoleucine. He was found to have a novel intronic change c.288+9C>T in the BCKDHA gene on one allele and p.G249S, a mutation previously associated with severe phenotype on the other [69]. He was found to have variably spliced products, including some normal mRNA. In the E1β gene, many mutations were found in Japanese [67]. An 11 base-pair deletion in the mitochondrial target sequence is relatively common [70]. Five mutations were found [68] in Portuguese, three of them nonsense, p.P200X, Q267Y, and R285X.
Reduced branched-chain aminotransferase activity alleviates metabolic vulnerability caused by dim light exposure at night in Drosophila
Published in Journal of Neurogenetics, 2023
Mari Kim, Gwang-Ic Son, Yun-Ho Cho, Gye-Hyeong Kim, Sung-Eun Yoon, Young-Joon Kim, Jongkyeong Chung, Eunil Lee, Joong-Jean Park
BCAT and BCKDHA/B complexes convert BCAAs to branched-chain acyl-CoA used for ATP generation through the TCA cycle (Figure 3(B)). The decrease in BCAA levels in Drosophila exposed to dim LAN may be due to the increased activity of these enzymes. To assess this possibility, we checked the mRNA levels of Bcat, bckdhA, and backhB, which encode BCAA metabolizing enzymes. The expression levels of these genes increased significantly in fly bodies at ZT 24 after exposure to dim light compared with those in the control group (Figure 3(C); CG1673, p < 0.05; CG8199, p < 0.01; CG17691, p < 0.05). In addition, Bcat expression showed a daily oscillation without LAN but increased significantly at ZT 18 and ZT 22 with LAN (Figure 3(D); ZT 18 and ZT 22, p < 0.05).
Effects of PPM1K rs1440581 and rs7678928 on serum branched-chain amino acid levels and risk of cardiovascular disease
Published in Annals of Medicine, 2021
Wen Hu, Ziyu Liu, Weinan Yu, Surong Wen, Xiaoqing Wang, Xing Qi, Hairong Hao, Yanwen Lu, Jing Li, Shayan Li, Hongwen Zhou
PPM1K is a kind of branched chain α-ketoacid (BCKA) dehydrogenase phosphatase and acts importantly in the metabolism of BCAAs by dephosphorylating BCKDHA. Mutations in PPM1K can increase the circulating BCAA levels and lead to an intermittent form of maple diabetes (MSUD) [5]. A GWAS study in Caucasians shows that a variant rs1440581 located upstream of PPM1K is a top SNP affecting circulating BCAA levels, while rs7678928 is also associated with Ile level [7]. As far as we know, few studies have been conducted to investigate the associations of rs1440581 and rs7678928 with serum BCAA levels in Chinese population.