Adenylate kinase (AK) deficiency is a rare erythroenzymopathy associated with hereditary nonspherocytic haemolytic anaemia along with mental/psychomotor retardation in few cases. Diagnosis of AK deficiency depends on the decreased level of enzyme activity in red cell and identification of a mutation in the AK1 gene. Until, only eight mutations causing AK deficiency have been reported in the literature. We are reporting two novel missense mutation (c.71A > G and c.413G > A) detected in the AK1 gene by next-generation sequencing (NGS) in a 6-year-old male child from India. Red cell AK enzyme activity was found to be 30% normal. We have screened a total of 32 family members of the patient and showed reduced red cell enzyme activity and confirm mutations by Sanger’s sequencing. On the basis of Sanger sequencing, we suggest that the proband has inherited a mutation in AK1 gene exon 4 c.71A > G (p.Gln24Arg) from paternal family and exon 6 c.413G > A (p.Arg138His) from maternal family. Bioinformatics tools, such as SIFT, Polymorphism Phenotyping v.2, Mutation Taster, MutPred, also confirmed the deleterious effect of both the mutations. Molecular modelling suggests that the structural changes induced by p.Gln24Arg and p.Arg138His are pathogenic variants having a direct impact on the structural arrangement of the region close to the active site of the enzyme. In conclusion, NGS will be the best solution for diagnosis of very rare disorders leading to better management of the disease. This is the first report of the red cell AK deficiency from the Indian population.
- adenylate kinase deficiency
- hereditary nonspherocytic haemolytic anaemia
- next-generation sequencing
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Handling editor Mary Frances McMullin.
Contributors RD, PW, RD, and PK performed experiments; PW and PSK collected and analysed data, and PSK wrote the manuscript; MRM gave technical support and conceptual advice. PP, PJ, NW, RS, KM, MVM are clinicians and involved in the blood transfusion and these authors play a role in the clinical management team. All authors read and approved the final manuscript.
Funding This study was funded by the Indian Council of Medical Research and Department of Biotechnology, Ministry of Science and Technology (Grant no. BT/PR20782/MED/12/737/16).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval This study was approved by the Ethics Review Board of the National Institute of Immunohematology (ICMR) Mumbai. Written informed consent was obtained from all patients before blood collection, and all samples were stored according to the principles of the Declaration of Helsinki.
Provenance and peer review Not commissioned; externally peer reviewed.