One missense mutation in exon 2 of the PAX5 gene in Iran

Abstract

ABSTRACT. The PAX5 gene, which encodes the B-cell specific activator protein, is one of the most important factors in determination of B-cell development. This gene is the main target of somatic mutations in acute B lymphoblastic leukemia (B-ALL). For example, point mutations, deletions, as well as other gene rearrangements may lead to several forms of B-cell malignancy. In this study, we obtained 50 blood samples from patients diagnosed with ALL, and screened for PAX5 mutations using sequencing in exons 1, 2 and 3. We found a heterozygous germline variant, c.113G>A (p.Arg38His), which affects the paired domain of PAX5. It seems that this mutation is pathogenic, but is recessive. Our findings suggest that this mutation in a single allele of the PAX5 gene is not sufficient to cause disease, and it is possible that other alleles are also involved in the onset of B-ALL.

Germline PAX5 mutation predisposes to familial B-cell precursor acute lymphoblastic leukemia

“…As described in other germline PAX5 pedigrees [6][7][8] , the existence of asymptomatic carriers and the absence of immunodeficiency before the onset of BCP-ALL suggest the requirement of additional genetic alterations leading to the development of leukemia. Subjects II.2 and II.3 had a normal karyotype at the BCP-ALL stage.…”

“…The onset of BCP-ALL in patients with PAX5 G183S germline mutations located in the octapeptide domain is very early with a median age of 2 years old and associated with a loss of the chromosome 9p leading to the simultaneous losses of the second PAX5 allele and CDKN2A 6,7 . In contrast, the germline R38H variant (this work and 8 ) is associated with an older age of onset (11 to 25 years old) and a normal karyotype (Supplemental Figure 5 and Supplemental Table 5).…”

“…This mutation was subsequently detected in all affected subjects, at the BCP-ALL diagnosis and at remission, and in one asymptomatic parent without history of malignancy (Figure 1B, Supplemental Figure 1 and Supplemental Table 3). PAX5 somatic alterations are present in one third of sporadic BCP-ALL 4,5 but only recently, PAX5 germline mutations leading to BCP-ALL have been identified [6][7][8] . PAX5 encodes a critical transcription factor for B-cell differentiation [9][10][11] repressing B-lineage 'inappropriate' gene expression and promoting the transcription of specific B-cell genes [10][11][12][13][14] .…”

A novel germline PAX5 single exon deletion in a pediatric patient with precursor B-cell leukemia

“…A germline PAX5 missense variant affecting the same hotspot, c.547G>C (p.Gly183Arg), has been reported in one family [ 9 ]. Two unrelated families were found to carry a germline c.113G>A (p.Arg38His) variant [ 7 , 8 ]. Functional studies showed that PAX5 p.Arg38His is also a hypomorphic variant resulting in incomplete B-cell differentiation and is sufficient to predispose to leukemia [ 8 ].…”

Forward and Reverse Genetics of B Cell Malignancies: From Insertional Mutagenesis to CRISPR-Cas

“…Karyotypic analysis indicates translocations are early events whereas deletion of a second allele appears to be a secondary later event. Germline point mutations that inhibit PAX5 function also increase the likelihood of B ALL and some are accompanied by somatic deletion of the other PAX5 allele or cooperating PAX5 mutations (112)(113)(114)(115). The discovery of frequent PAX5 deletion and translocations in human ALL was rapidly followed by a large number of studies using some form of Pax5 deletion or translocation in mice to model B ALL.…”