# SERPINB3, Adult-Onset Immunodeficiency, and Generalized Pustular Sporiasis
## 4 Discussion  
### SERPINB3 Variants and GPP and AOID Phenotypes  
In this study, we report three unrelated Thai patients: two with AOID and the third with GPP. Patients 1 and 2 who had AOID with pushular reaction and GPP, respectively, carried the same heterozygous missense variant c.438G>T; p.Lys146 Asn in _SERPINB3_, suggesting shared pathogenetic pathways between GPP and AOID. Patient 3 who was affected with AOID carried a novel heterozygous missense variant c.917A>G; p.Asp306 Gly in _SERPINB3_. Our findings raise an interesting question of whether both _SERPINB3_ variants were implicated in GPP and AOID phenotypes or were just coincidental findings. We have reason to believe that these variants are implicated in GPP and AOID. First, _SERPINB3_, _SERPINA1_, and _SERPINA3_ are homologous and share inhibitory function, and genetic variants in _SERPINA1 and SERPINA3_ have been reported to be the \"predisposing risk factors\" for GPP [4; 5] and AOID [3]. Second, the c.438G>T; p.Lys146 Asn variant found in the two unrelated patients is very rare in the general population. According to gnomAD, its allele frequency is 0.0002126, and it is not seen in 30598 alleles in the South Asian population. It was detected in two of 720 Thai individuals who did not have a history of pustular reaction in our in-house exome database (allele frequency = 0.00069444). Third, the amino acid p.Lys146 residue is highly conserved (Figure 2A). The in silico model of the p.Lys146 Asn variant revealed that the substitution of Lys146 with Asn altered the formation of the salt bridge between helix F and \(\beta\)-sheet A. The cluster of interacting residues in both helix F and \(\beta\)-sheet A was proposed to be significant for maintaining structural stability and thus increases resistance in polymerization [22; 23]. Notably, the mutation in helix F appeared to accelerate the polymerization process in certain SERPIN proteins [24] (Figure 5). This mutation is predicted to be deleterious (0.01) and probably damaging (0.991) with SIFT and PolyPhen, respectively (Table 1).  
The c.917A>G; NP_008850.1p.Asp306 Gly variant in _SERPINB3_, which was identified in patient 3 affected with AOID, appears to be novel. It was not reported in the gnomAD and LOVD databases. It was not found in the 720 Thai individuals of our in-house exome database. The mutation is predicted to be deleterious (0) and possibly damaging (0.889), with SIFT and PolyPhen, respectively (Table 1).  
The amino acid Asp306 residue is highly conserved (Figure 2B). The in silico protein modeling of the dimer structure of _SERPINB3_ proteins shows that the amino acid Asp306 residue is located at a flexible loop region. The glycine substitution in this loop region could cause an increase in the overall structural flexibility of the loop area. This may lead to an increase in conformational liability and formation of the M* state, resulting in a possible rise in SERPIN polymerization [18] (Figure 6).  
Figure 5: The point mutation at Lys146 alters the salt bridge formation between helix-F and \(\beta\)-sheet A. (**A**) Superimposition of the homology-based 3D models of the SERPINB3 and its p.Lys146 Asn variant (K146N) showing the position of amino acid residue-146 and its inter-reacting partners. The normal SERPINB3 is colored in green, and the p.Lys146 Asn variant is colored in salmon. (**B**) The expanded view of the selected area in A revealed the network of salt bridges between Lys146 and highly conserved Glu132 and Lys106. The disruption of this interaction network caused by the Asn substitution could significantly alter the stability of the SERPIN structure.