GD is an autoimmune disease with complex etiology. With the extensive development of GWAS research, many GD susceptibility genes have been identified such as HLA, CTLA4, PTPN22, and TSHR[9]. Gene mutations may affect the antigen presentation, T cell signal transduction, B cell antibody production, thyroid hormone, and thyroid-related apoptosis which may lead to the occurrence of GD. The gene mutation effects provide a theoretical basis for GD's precise diagnosis and treatment. However, the current impact of GD susceptibility gene polymorphism on the expression of corresponding proteins is still unknown and research on the interaction between genes is limited in elucidating the role of gene polymorphism in disease pathogenesis.
In the case study, it presents a rare familial GD case in 5 patients in a three-generation family. The five patients are consistent with the general characteristic of GD patients which is that the GD is prone to attack women at the age of 30-60 [10]. All the members of the three-generation family came from the same district of Zhanjiang city and they have been living in similar environment which guarantees the consistency of environmental factors in this case study. Although the etiology of GD is complex and clear identification of potential factors for GD has not been completed, it is widely recognized that the genetic determinants such as HLA, CTLA-4, PTPN22, and CD40 have contributed to the risk of GD[11]. However, no variation of these former identified genes was found, but the following variations of MAP7D2, SLC1A7, TRAF3IP3, PTPRB, PIK3R3, DISC1, and SUPT20HL were found in the familial GD. Furthermore, the variations in PTPRB, PIK3R3, and TRAF3IP3 were predicted to have alter the functions of the encoded protein. Familial GD of multigeneration is important for heritable studies because it avoids the genetic heterogeneity factor, so this case study may explain the genetic cause of the familial clustering of GD.
MAP7D2 (MAP7 domain containing 2) is located on X chromosome. MAP7D2 is specifically expressed in human brain tissue which has impact on the behavioral traits and cognition in human. MAP7D2 is also associated with sex-biased mental illnesses[12]. Previous studies has shown that gender predisposition to GD is associated with X chromosome inactivation (XCI) migration[13]. Thus, the MAP7D2 study is likely to provide important general information about the reason why women are more vulnerable to GD. SLC1A7 and DISC1 are also susceptibility genes for mental illnesses. In one research, Keith A. Young et al. discovered that DISC1 gene played a vital role in post-traumatic stress disorder (PTSD) severity of US military veterans[14]. In another research, Fujita K, et al. revealed that SLC1A7 gene expression in peripheral blood leukocytes was responsible for the association between socioeconomic status and depressive mood in healthy adults[15]. We speculated that SLC1A7 and DISC1 are involved in regulating the symptoms of GD such as nervousness and irritability.
The protein encoded by PTPRB belongs to the family of protein tyrosine phosphatases (PTP). The activation of PTK (protein tyrosine kinase) was regulated through the binding of SH2 domains from PI3K(PIK3R3 gene encode). The balance of tyrosine protein phosphorylation was regulated by PTP/PTK which participated in cell signal transduction, cell growth regulation, differentiation, metabolism, transcription, immune responses, etc. Researches have demonstrated that the significant role of PTKs and PTPs were to modulate the tyrosine phosphorylation-dependent signaling pathways which were critical for the effector of NK cell and Neutrophil cell[16,17]. TRAF3IP3 is also highly expressed in CD34+CD38+CD7+ common lymphoid progenitors (CLPs) Furthermore, CD34+CD38+CD7+ cells have the capacity to differentiate into B/NK/T cell which implies that TRAF3IP3 possibly may play a role in lymphoid development [18]. The overactivation of the T/B cell was regulated by CTLA-4 and CD40 gene variants which has been confirmed in the pathogenesis of autoimmune diseases including GD. Therefore, further studies are necessary to figure out whether the variations of PTPRB, PIK3R3 and TRAF3IP3 are involved in the dysfunction of thyroid autoimmune.
The case study is about the susceptibility genes of a single three-generation family of Graves disease, but there are insufficient samples of similar families to verify the results of this study. Also, the frequency of susceptibility genes screened in this study has not been further verified in the population of patients with sporadic Graves disease and the relationship between these gene mutations and sporadic Graves disease is uncertain. Finally, the susceptibility genes screened this time need to be further studied at the protein molecular level to further determine the biological significance of these mutations.