Author:
He Sijia,Chen Hongbo,Guo Xia,Gao Ju
Abstract
Abstract
Background
Adenylate kinase (AK) is a monomolecular enzyme widely found in a variety of organisms. It mainly catalyses the reversible transfer of adenosine nucleotide phosphate groups and plays an important role in maintaining energy metabolism. AK deficiency is a rare genetic disorder that is related to haemolytic anaemia. Chronic haemolytic anaemia associated with AK deficiency is a rare condition, and only 14 unrelated families have been reported thus far. Moreover, only 11 mutations have been identified in the AK1 gene, with only 3 cases of psychomotor impairment.
Case presentation
The patient was a 3-year-old boy with severe haemolytic anaemia and psychomotor retardation. A molecular study of the patient’s AK gene revealed 2 different mutations: a heterozygous missense mutation in exon 6 (c.413G > A) and a heterozygous frameshift mutation in exon 5 (c.223dupA). Molecular modelling analyses indicated that AK gene inactivation resulted in a lack of AK activity. The patient recovered after regular blood transfusion therapy.
Conclusions
AK1 deficiency was diagnosed on the basis of low enzymatic activity and the identification of a mutation in the AK1 gene located on chromosome 9q. Here, we report the first case of moderate red cell AK1 deficiency associated with chronic nonspherocytic haemolytic anaemia (CNSHA) in China. The genetic mutations were confirmed by Sanger sequencing. The variants were classified as pathogenic by bioinformatics tools, such as ACMG/AMP guidelines, Mutation Taster, SIFT, MACP, REVEL and PolyPhen2.2. Based on our evidence and previous literature reports, we speculate that the site of the AK1 gene c.413G > A (p.Arg138His) mutation may be a high-frequency mutation site and the other mutation (c.223dupA) might be related to the neuropathogenicity caused by AK1 deficiency. NGS should be a part of newborn to early childhood screening to diagnose rare and poorly diagnosed genetic diseases as early as possible.
Funder
Department of Science and Technology of Sichuan Province
Chengdu Science and Technology Bureau
Publisher
Springer Science and Business Media LLC
Subject
Genetics (clinical),Genetics
Reference32 articles.
1. Deline ML, Grashei M, van Heijster FHA, Schilling F, Straub J, Fromme T. Adenylate kinase derived ATP shapes respiration and calcium storage of isolated mitochondria. Biochim Biophys Acta Bioenerg. 2021;1862(7):148409.
2. Chou J, Alazami AM, Jaber F, Hoyos-Bachiloglu R, Jones J, Weeks S, Alosaimi MF, Bainter W, Cangemi B, Badran YR, et al. Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B cell activation. J Allergy Clin Immunol. 2019;146(1):192–202.
3. Kong J, Li J, Lu J, Li W, Wang W. Role of substrate-product frustration on enzyme functional dynamics. Phys Rev E. 2019;100(5–1):052409.
4. Muller WEG, Wang S, Neufurth M, Kokkinopoulou M, Feng Q, Schroder HC, Wang X. Polyphosphate as a donor of high-energy phosphate for the synthesis of ADP and ATP. J Cell Sci. 2017;130(16):2747–56.
5. Wang J, Peng C, Yu Y, Chen Z, Xu Z, Cai T, Shao Q, Shi J, Zhu W. Exploring conformational change of adenylate kinase by replica exchange molecular dynamic simulation. Biophys J. 2020;118(5):1009–18.
Cited by
2 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献