ABSTRACT
Over the past few years, there has been a notable increment in scientific literature aimed at unraveling the genetic foundations of vitamin D signaling and its implications for susceptibility to autoimmunity, however, most of them address isolated diseases. Here, we conducted a systematic review of genetic variants related to vitamin D and autoimmune diseases and we discussed the current landscape of susceptibility and outcomes. Of 65 studies analyzed, most variants cited are in vitamin D binding protein (VDBP; rs2282679 GC gene), 25-hydroxylase (rs10751657 CYP2R1), 1α-hydroxylase (rs10877012, CYP27B1) and the nuclear hormone receptor superfamily [FokI (rs2228570), BsmI (rs1544410), ApaI (rs7975232), and TaqI (rs731236) in VDR gene]. Therefore, our findings confirmed the associations of several genetic variants of vitamin D signaling with a broad spectrum of autoimmune diseases/traits. In addition, given the low number of papers found with functional analysis, further studies to elucidate the real effect that the variants exert on Vitamin D signaling are recommended.
ABSTRACT
Cerebral cavernous malformation (CCM) is a vascular disease that affects the central nervous system, which familial form is due to autosomal dominant mutations in the genes KRIT1(CCM1), MGC4607(CCM2), and PDCD10(CCM3). Patients affected by the PDCD10 mutations usually have the onset of symptoms at an early age and a more aggressive phenotype. The aim of this study is to investigate the molecular mechanism involved with CCM3 disease pathogenesis. Herein, we report two typical cases of CCM3 phenotype and compare the clinical and neuroradiological findings with five patients with a familial form of KRIT1 or CCM2 mutations and six patients with a sporadic form. In addition, we evaluated the PDCD10 gene expression by qPCR and developed a bioinformatic pipeline to understand the structural changes of mutations. The two CCM3 patients had an early onset of symptoms and a high lesion burden. Furthermore, the sequencing showed that Patient 1 had a frameshift mutation in c.222delT; p.(Asn75Thrfs*14) that leads to lacking the last 124 C-terminal amino acids on its primary structure and Patient 2 had a variant on the splicing site region c.475-2A > G. The mRNA expression was fourfold lower in both patients with PDCD10 mutation. Using in silico analysis, we identify that the frameshift mutation transcript lacks the C-terminal FAT-homology domain compared to the wild-type PDCD10 and preserves the N-terminal dimerization domain. The two patients studied here allow estimating the potential impact of mutations in clinical interpretation as well as support to better understand the mechanism and pathogenesis of CCM3.
