A synonymous mutation in PI4KA impacts the transcription and translation process of gene expression

• Published in: Frontiers in immunology 2022-10, Vol.13, p.987666-987666
• Main Authors: Zhang, Kaihui, Kang, Lili, Zhang, Haozheng, Bai, Lu, Pang, Huanping, Liu, Qinghua, Zhang, Xinyi, Chen, Dong, Yu, Haihua, Lv, Yuqiang, Gao, Min, Liu, Yi, Gai, Zhongtao, Wang, Dong, Li, Xiaoying
• Format: Article
• Language: English
• Subjects: Alternative Splicing; Child; diarrheal; Gene Expression; Humans; immunodeficiency; Immunology; Infant, Newborn; minigene splicing assay; Mutation; PI4KA; RNA Splicing; Silent Mutation; synonymous mutation
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2022.987666

Phosphatidylinositol-4-kinase alpha (PI4KIIIα), encoded by the gene, can synthesize phosphatidylinositol-4-phosphate (PI-4-P), which serves as a specific membrane marker and is instrumental in signal transduction. mutations can cause autosomal recessive diseases involving neurological, intestinal, and immunological conditions (OMIM:619621, 616531, 619708). We detected sepsis, severe diarrhea, and decreased immunoglobulin levels in one neonate. Two novel compound heterozygous mutations, c.5846T>C (p.Leu1949Pro) and c.3453C>T (p.Gly1151=), were identified in the neonate from the father and the mother, respectively. Sanger sequencing and reverse transcription polymerase chain reaction (RT-PCR) for peripheral blood and minigene splicing assays showed a deletion of five bases (GTGAG) with the c.3453C>T variant at the mRNA level, which could result in a truncated protein (p.Gly1151GlyfsTer17). The missense mutation c.5846T>C (p.Leu1949Pro) kinase activity was measured, and little or no catalytic activity was detected. According to the clinical characteristics and gene mutations with functional verification, our pediatricians diagnosed the child with a combined immunodeficiency and intestinal disorder close to gastrointestinal defects and immunodeficiency syndrome 2 (GIDID2; OMIM: 619708). Medicines such as immunomodulators are prescribed to balance immune dysregulation. This study is the first report of a synonymous mutation in the gene that influences alternative splicing. Our findings expand the mutation spectrum leading to PI4KIIIa deficiency-related diseases and provide exact information for genetic counseling.