IgA nephropathy, the most common primary glomerulonephritis, was considered as a polygenic and multifactorial disorder. There were extensive evidences suggested the genetic components were involved in the susceptibility and progression of IgAN [5
]. The pathogenesis of IgAN was still indistinct, as far as we knew. Fortunately, more and more evidences suggested that deficient β
1,3 galactosylation of hinge region of IgA1 molecule played an important role in the pathogenesis of IgAN in recent years [4
The galactosylation of GalNAcα1-R in hinge region of IgA1 molecule depended on the activity of C1β
3Gal-T. Intriguingly, patients with IgAN had normal expression of C1GALT1
gene and decreased expression of C1GALT1C1
]. Furthermore, diseases resulted from deficiency of β
1,3 galactose, such as Tn syndrome, weren't a result of decreased expression of C1GALT1
gene, but resulted from the mutations of C1GALT1C1
]. These results suggested that it was rather the variants of C1GALT1C1
gene in influencing the galactosylation of IgA1 hinge-region than the variants of C1GALT1
gene. It implies that the variants of C1GALT1C1
gene could contribute to susceptibility of IgAN by influencing β
1,3 galactosylation of IgA1 molecule. Our previous study revealed that there was only one SNP, c.393T>A (rs17261572), in coding region of C1GALT1C1
]. It was a nonsynonymous SNP. The MAF of c.393T>A was only 0.069. A previous study revealed that the mutations weren't important for the European IgAN patients [16
]. Were the mutations (including somatic mutation) in the promoter region important in the pathogenesis of IgAN in China? Therefore, we designed a study to test the hypothesis.
We firstly screened the polymorphisms of C1GALT1C1 gene in promoter region. One SNP, c.-347-190G>A was detected. And its MAF was 48.48%. Therefore, association between the c.-347-190G>A polymorphism and IgAN was explored in a case-control association study in a large population sampled from the Northern Chinese. The association analysis revealed that there was no significant difference of the alleles between the controls and the IgAN patients in total samples or in two sub-group samples divided by genders. There was only a weak association between the genotypes of c.-347-190G>A (GG/GA) and IgAN detected in female cases. But the positive association wasn't replicated in male sample simultaneously. The C1GALT1C1 gene located on chromosome X, so the effect of polymorphisms would be influenced by the inactivity of sex chromosome. The positive association might not demonstrate a truly causal association between the SNP and IgAN. These results suggested that polymorphisms of C1GALT1C1 gene might not be related to the susceptibility of IgAN.
In present study, we further analyzed the association between the SNP of C1GALT1C1 gene and clinical parameters of IgAN. The results revealed that there was no significant difference of blood pressure, proteinuria, and renal function among the IgAN patients with different genotypes. These data suggested that the genotypes of the C1GALT1C1 gene did not influence the clinical manifestations of IgAN.
In previous studies of Tn syndrome, three somatic mutations of C1GALT1C1
gene were identified in two patients. The three somatic mutations, c.202C>T, c.393T>A and c.454G>A, were all in the coding region of C1GALT1C1
]. Except the c.393T>A mutation, both of the other two somatic mutations could impressively inhibit chaperone activity and lead to inactivation of C1β
3Gal-T, and the expression of autoimmune Tn antigen on blood cells of all lineages[14
]. Galactosylation deficiency was already proved in patients with IgAN. Does somatic mutation exist in C1GALT1C1
gene in patient with IgAN too?
In order to prove this hypothesis, we furthermore performed a somatic mutation screening in the patients with IgAN. DNAs from B lymphocytes where IgA molecule was produced were isolated from 22 individuals. And then the coding region of C1GALT1C1
gene was amplified, cloned and sequenced. Except the c.393T>A, no other mutations were detected. The mutation, c.393T>A, was only found in the patients whose mutations were demonstrated in genomic DNA by routinely sequencing. Furthermore, c.393T>A was proved not to be a somatic mutation in these IgAN patients. The result indicated that the variation of coding region of C1GALT1C1
gene might be of little importance in the processing of aberrant glycosylation of IgA1 molecule in patients with IgAN. Mutations in other regions of C1GALT1C1
gene, which may influence the glycosylation process of IgA1 molecule, were needed to be clarified in patients with IgAN. In fact, in a recent study, Malychaet al [16
] detected mutations in whole blood DNA and in B cell DNA separately in a relative small European sample. They didn't found any important mutations of C1GALT1C1
gene in patients with IgAN. These results suggested that the C1GALT1C1
gene might influence the susceptibility to IgAN by an alternative pathway if it was important for IgAN.