Human MSH6 Deficiency Is Associated with Impaired Antibody Maturation

Abstract

Ig class-switch recombination (Ig-CSR) deficiencies are rare primary immunodeficiencies characterized by defective switched isotype (IgG/IgA/IgE) production. Depending on the molecular defect, defective Ig-CSR may also be associated with impaired somatic hypermutation (SHM) of the Ig V regions. Although the mechanisms underlying Ig-CSR and SHM in humans have been revealed (at least in part) by studying natural mutants, the role of mismatch repair in this process has not been fully elucidated. We studied in vivo and in vitro Ab maturation in eight MSH6-deficient patients. The skewed SHM pattern strongly suggests that MSH6 is involved in the human SHM process. Ig-CSR was found to be partially defective in vivo and markedly impaired in vitro. The resolution of γH2AX foci following irradiation of MSH6-deficient B cell lines was also found to be impaired. These data suggest that in human CSR, MSH6 is involved in both the induction and repair of DNA double-strand breaks in switch regions.

Diagnostic criteria for constitutional mismatch repair deficiency syndrome: suggestions of the European consortium ‘Care for CMMRD’ (C4CMMRD)

“…An analysis of three patients with biallelic PMS2 and eight with biallelic MSH6 mutations has shown that constitutional deficiency of these MMR genes leads to impaired immunoglobulin (Ig) class switch recombination characterised by a decrease or absence of IgG2, IgG4 and IgA concomitant (particularly in young patients) with increased IgM levels, that is, hyper-IgM syndrome 36 37. IgA deficiency indicative of this humoral defect was also observed in a patient with a homozygous MSH2 mutation 38.…”

Antibody diversification caused by disrupted mismatch repair and promiscuous DNA polymerases

“…The MutSα-deficient mice exhibit an altered mutation spectrum, with a 75-90% decrease in mutations at A:T bp [44, 45, 48]. A marked decline in A:T mutagenesis has also been observed in MSH6-deficient humans [49]. Exo1 −/− mice have decreased SHM and mutations at A:T bp [50, 51].…”

Agenesis of the corpus callosum and gray matter heterotopia in three patients with constitutional mismatch repair deficiency syndrome

“…Furthermore, defects in immunoglobulin class switch recombination (indicated by decreased levels or absence of IgG2, IgG4 and IgA together with increased IgM levels) are also associated with CMMR-D syndrome. 10,11 At least one CMMR-D patient initially presented with a primary immunodeficiency. 11 Despite publication of 4100 CMMR-D patients, diagnosis may still be delayed in many childhood cancer patients.…”