Journal Article

Genetic evidence for predisposition to acute leukemias due to a missense mutation (p.Ser518Arg) in ZAP70 kinase: a case-control study

Naeimi, Leila, Rahimzadeh, Masoomeh, Khashei Varnamkhasti, Samire, Naeimi, Sirous, Khashei Varnamkhasti, Khalil, Naeimi, Behrouz, Shahrouzian, Atefeh

2024

Overview

Background The apparent lack of additional missense mutations data on mixed-phenotype leukemia is noteworthy. Single amino acid substitution by these non-synonymous single nucleotide variations can be related to many pathological conditions and may influence susceptibility to disease. This case-control study aimed to unravel whether the ZAP70 missense variant (rs104893674 (C > A)) underpinning mixed-phenotype leukemia. Methods The rs104893674 was genotyped in clients who were mixed-phenotype acute leukemia-, acute lymphoblastic leukemia- and acute myeloid leukemia-positive and matched healthy controls, which have been referred to all major urban hospitals from multiple provinces of country- wide, IRAN, from February 11’ 2019 to June 10’ 2023, by amplification refractory mutation system-polymerase chain reaction method. Direct sequencing for rs104893674 of the ZAP70 gene was performed in a 3130 Genetic Analyzer. Results We found that the AC genotype of individuals with A allele at this polymorphic site (heterozygous variant-type) contribute to the genetic susceptibility to acute leukemia of both forms, acute myeloid leukemia and acute lymphoblastic leukemia as well as with a mixed phenotype. In other words, the ZAP70 missense variant (rs104893674 (C > A)) increases susceptibility of distinct cell populations of different (myeloid and lymphoid) lineages to exhibiting cancer phenotype. The results were all consistent with genotype data obtained using a direct DNA sequencing technique. Conclusion Of special interest are pathogenic missense mutations, since they generate variants that cause specific molecular phenotypes through protein destabilization. Overall, we discovered that the rs104893674 (C > A) variant chance in causing mixed-phenotype leukemia is relatively high.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Acute lymphoblastic leukemia / Acute myeloid leukemia / Adolescent / Adult / Amino acid substitution / Amino acids / Analysis / Biomedical and Life Sciences / Biomedicine / Blood tests / Case-Control Studies / Disease susceptibility / DNA sequencing / Equilibrium / Ethylenediaminetetraacetic acid / Female / Flow cytometry / Gene Expression / Gene mutations / Genes / Genetic aspects / Genetic Predisposition to Disease / Genotype / Genotype & phenotype / Genotypes / Health aspects / Hematology / Human Genetics / Humans / Kinases / Leukemia / Leukemia, Myeloid, Acute - genetics / Lymphatic leukemia / Male / Medical prognosis / Medical research / Medicine, Experimental / Microarrays / Middle Aged / Missense mutation / Mixed phenotype acute leukemia / Mutation / Mutation, Missense / Nucleotide sequencing / Phenotypes / Phenotypic variations / Physiological aspects / Polymerase chain reaction / Polymorphism / Polymorphism, Single Nucleotide / Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics / Protein kinases / Proteins / Risk factors / rs104893674 (C > A) / Sample size / Thermal cycling / Young Adult / ZAP-70 protein / ZAP-70 Protein-Tyrosine Kinase - genetics / ZAP70 gene