The plasma proteome changes observed in the Atp7b-/- mouse were not confirmed in these samples, except for alpha-1 antichymotrypsin, levels of which were decreased in WD patients compared to healthy individuals.
Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2.
For this reason, we investigate whether or not Kyn and IDO activity is potentially useful biomarkers in pediatric AIH.Between January 2016 and January 2017, children of AIH type-1 (AIH-1, n = 37), AIH type-2 with liver kidney microsome-1 autoantibodies (AIH-2-LKM-1, n = 8), and autoantibody-negative Wilsons Disease (WD, n = 8) and alpha-1 anti-trypsin deficiency (AATD, n = 10), were enrolled in a cross-sectional survey of Kyn and Trp levels and Kyn/Trp ratios (IDO activity) by HPLC, and neopterin levels by ELISA.The mean Kyn and mean Kyn/Trp ratios of AIH-1 with smooth muscle antigen (SMA) 1.85 μM and 27 μmole/mmole, and AIH-2-LKM-1; 1.7 μM and 28.6 μmole/mmole were lower than that of the WD; 2.2 μM p = 0.03 and 33 μmole/mmole p = 0.02 and of AATD; 2.3 μM, p = 0.02 and 55 μM, p = 0.001.
For this reason, we investigate whether or not Kyn and IDO activity is potentially useful biomarkers in pediatric AIH.Between January 2016 and January 2017, children of AIH type-1 (AIH-1, n = 37), AIH type-2 with liver kidney microsome-1 autoantibodies (AIH-2-LKM-1, n = 8), and autoantibody-negative Wilsons Disease (WD, n = 8) and alpha-1 anti-trypsin deficiency (AATD, n = 10), were enrolled in a cross-sectional survey of Kyn and Trp levels and Kyn/Trp ratios (IDO activity) by HPLC, and neopterin levels by ELISA.The mean Kyn and mean Kyn/Trp ratios of AIH-1 with smooth muscle antigen (SMA) 1.85 μM and 27 μmole/mmole, and AIH-2-LKM-1; 1.7 μM and 28.6 μmole/mmole were lower than that of the WD; 2.2 μM p = 0.03 and 33 μmole/mmole p = 0.02 and of AATD; 2.3 μM, p = 0.02 and 55 μM, p = 0.001.
Further, through gene expression profiling, detection of β-catenin in total protein and nuclear protein, and the nuclear localization of β-catenin, we identified and validated that low osteogenic activity in WD may be due to abnormal β-catenin pathway.
Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2.
In particular, non-random occurrence was revealed for SERPINA1 c.1096G > A (alpha-1 antitrypsin deficiency), C8B c.1282C > T and c.1653G > A (complement component 8B deficiency), ATP7B c.3207C > A (Wilson disease), PROP1c.301_302delAG (combined pituitary hormone deficiency), CYP21A2 c.844G > T (non-classical form of adrenogenital syndrome), EYS c.1155T > A (retinitis pigmentosa), HADHA c.1528G > C (LCHAD deficiency), SCO2 c.418G > A (cytochrome c oxidase deficiency), OTOA c.2359G > T (sensorineural deafness), C2 c.839_866del (complement component 2 deficiency), ACADVL c.848T > C (VLCAD deficiency), TGM5 c.337G > T (acral peeling skin syndrome) and VWF c.2561 G > A (von Willebrand disease, type 2N).
Three polymorphisms of DBH (rs1611115 in the promoter, rs1108580 in exon 2 and rs129882 in 3'-UTR) were screened for their association with the clinical attributes (hepatic and neurological features) and age of onset of WD using a polymerase chain reaction-restriction fragment length polymorphsm method and sequencing approach.
In addition, the higher Th1 cells (IL-2, TNF-α, and TNF-β), Th2 cells (IL-13), and Th17 (TGF-β1, IL-23) and the course of WD were associated with the severity of the neurological symptoms for WD patients.
Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2.
In addition, the higher Th1 cells (IL-2, TNF-α, and TNF-β), Th2 cells (IL-13), and Th17 (TGF-β1, IL-23) and the course of WD were associated with the severity of the neurological symptoms for WD patients.
WD phenotype DMRs corresponded to genes enriched for functions in mental deterioration, abnormal B cell physiology, and as members of the polycomb repressive complex 1 (PRC1).
Functional annotation revealed that WD-hypermethylated liver DMRs were enriched in liver-specific enhancers, flanking active liver promoters, and binding sites of liver developmental transcription factors, including Hepatocyte Nuclear Factor 4 alpha (HNF4A), Retinoid X Receptor alpha (RXRA), Forkhead Box A1 (FOXA1), and FOXA2.
In addition, the higher Th1 cells (IL-2, TNF-α, and TNF-β), Th2 cells (IL-13), and Th17 (TGF-β1, IL-23) and the course of WD were associated with the severity of the neurological symptoms for WD patients.
We report statistically significant overrepresentation of pathogenic variants for several Mendelian disorders, including phenylketonuria (PAH, rs5030858), Wilson's disease (ATP7B, rs76151636), factor VII deficiency (F7, rs36209567), kyphoscoliosis type of Ehlers-Danlos syndrome (FKBP14, rs542489955), and several other recessive pathologies.