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

Abstract

Phosphatidylinositol-4-kinase alpha (PI4KIIIα), encoded by the PI4KA gene, can synthesize phosphatidylinositol-4-phosphate (PI-4-P), which serves as a specific membrane marker and is instrumental in signal transduction. PI4KA 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 PI4KA gene that influences alternative splicing. Our findings expand the mutation spectrum leading to PI4KIIIa deficiency-related diseases and provide exact information for genetic counseling.

Combination of Synonymous and Missense Mutations in JAK3 Gene Contributes to Severe Combined Immunodeficiency in One Child

“…The cDNA level with the c.1914G>T mutation results in only up to about 1/3 of the normal cDNA strand. This is similar to our previous synonymous mutation research [11], about which the minigene assay confirmed the nonsense-mediated mRNA decay (NMD), mediated downregulation, which contributes to about one-third of disease-causing mRNAs [12,13]. However, no possible abnormal splice patterns were predicted through splicing prediction software.…”

“…Synonymous mutations are frequently detected from gene sequencing and considered to be nonpathogenic as they do not alter the amino acid of the encoded protein. However, synonymous mutations could also lead to abnormal splicing by creating or altering noncanonical splicing sites, and there are quite a few reports about synonymous variations contributing to abnormal splicing [11]. In our study, the proband has the synonymous variant c.1914G>T (p. L638=) in the JAK3 gene which is inherited from her mother, with location at the 5′ end of exon 14, in which the nucleoside site is against the splicing donor site of the 5′ end of the intron which starts with the G. We speculated that the variant could disturb the donor splice site function.…”