Serum bile acid profiles of our VPS33B/VIPAS39 mutated patients revealed similar changes to primary defect of bile salt export pump, among which those with isolated cholestasis phenotype had a higher level of total secondary bile acids than that with typical ARC phenotype, indicating the partial residual function of VPS33B.
These results demonstrate that abnormal protein trafficking and impairment in MVB maturation in MKs underlie the α-granule deficiency in Vps33b(fl/fl)-ER(T2) mouse and ARC patients.
This study provides the first evidence of genotype-phenotype correlation in ARC and suggests that VPS33B c.1225+5G>C mutation predicts a mild ARC phenotype.
Thus we show that all patients with a classical clinical course of ARC had decreased expression of VPS33B whereas normal VPS33B expression was associated with good prognosis despite initial diagnosis of ARC.
VPS33B is involved in regulation of vesicular membrane fusion by interacting with SNARE proteins, and evidence of abnormal polarised membrane protein trafficking has been reported in ARC patients.
Alagille syndrome patients carry mutations in JAG1, and mutations in VPS33B have been identified in patients with arthrogryposis, renal dysfunction and cholestasis syndrome (ARC).
However, in MDR, the gene-gene interaction among the five SNPs (WRN-rs4733220 (G>A), WRN-rs1801195 (T>G), OGG1-rs2072668 (G>C) and OGG1-rs2304277 (A>G)) on ARC risk was significant (OR = 5.03, 95% CI: 3.54~7.13).
The results suggest that the Asn/Asn genotype and Asn³¹² allele of XPD polymorphism, as well as the Cys/Cys genotype and Cys³²⁶ allele of the OGG1 polymorphism, may be associated with increased risk of the development of ARC, particularly the cortical type, in the Egyptian population.
This study examined the associations of 18 single nucleotide polymorphisms (SNPs) in four DNA repair genes (BLM, WRN, ERCC6, and OGG1) with ARC in Han Chinese from the Jiangsu Eye Study, a population-based epidemiologic study.
The apoptosis inhibitor ARC undergoes ubiquitin-proteasomal-mediated degradation in response to death stimuli: identification of a degradation-resistant mutant.
However, in MDR, the gene-gene interaction among the five SNPs (WRN-rs4733220 (G>A), WRN-rs1801195 (T>G), OGG1-rs2072668 (G>C) and OGG1-rs2304277 (A>G)) on ARC risk was significant (OR = 5.03, 95% CI: 3.54~7.13).
Thus, our data suggest that the T allele of rs7278468 in the CRYAA promoter is associated with ARC through increasing binding of KLF-10 and thus decreasing CRYAA transcription.
Also, carrying the combined genotypes of GSTM 1 null, GSTT 1 and GSTP 1 105-Val allele was seen to have an increased risk of developing ARC (OR: 2.91, 95% CI: 1.31-6.44).