Polymorphism of Genes Involved in Purine Metabolism (XDH, AOX1, MOCOS) in Kidney Transplant Recipients Receiving Azathioprine

Kurzawski, Mateusz; Dziewanowski, Krzysztof; Safranow, Krzysztof; Droździk, Marek

doi:10.1097/ftd.0b013e31824aa681

Cited by 31 publications

(17 citation statements)

References 25 publications

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“…This finding is worthy of additional research, as there could be pharmacokinetic/pharmacodynamic drug interaction implications for alcoholics taking any drug that has a predominant clearance mechanism through AO. In addition to donor demographics and medical histories, a potential contributor to variable AO activity is the presence of SNPs, which are known and have been reported (Smith et al, 2009;Hartmann et al, 2012;Kurzawski et al, 2012). Whereas the two variants observed in our donor population (rs55754655 and rs3731722) have been reported to have clinical implications in use of azathioprine (Smith et al, 2009), the intrinsic clearance differences in our cohort did not reach statistical significance, despite a trend toward higher activity compared with wild-type individuals (Fig.…”

Section: Discussioncontrasting

confidence: 45%

Aldehyde Oxidase Activity in Donor-Matched Fresh and Cryopreserved Human Hepatocytes and Assessment of Variability in 75 Donors

et al. 2014

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Studies were conducted to evaluate the impact of time and cryopreservation on aldehyde oxidase (AO) activity in human hepatocytes isolated from 10 donor livers, using O 6 -benzylguanine as a probe substrate. In addition, variability in activity was assessed using cryopreserved hepatocytes from 75 donors. Substantial donor-dependent loss in AO activity within 24 hours after isolation of hepatocytes was observed (average loss of 42%, range 15%-81%). Meanwhile, AO activity in cryopreserved hepatocytes more closely represented the activity observed in fresh hepatocytes that were incubated immediately after isolation for the same donors (within 81% of fresh, range 48%-100%). Activity of AO in cryopreserved hepatocytes from 75 donors varied by at least 17-fold (£ 5.4 to 90 ml/minute per kilogram of body weight), with 63% of the donors having higher activity than a pooled 19-donor lot (34.2 ml/minute per kilogram). Comparison of demographics such as gender, body mass index, age, and ethnicity showed no statistically significant correlations with activity. Evaluation of medical histories revealed that three of the five donors with no measurable activity had immediate histories of extensive alcohol abuse. Meanwhile, two single nucleotide polymorphisms (SNPs) for AOX1 (rs3731772 and rs55754655) were detected in our donor pool and showed allelic frequencies similar to those reported from other cohort studies. However, these SNPs did not correlate with a statistically significant difference in intrinsic clearance compared with wild-type donors. With a general lack of clarity about what causes highly variable AO activity, prescreening donors for AO activity and creating a custom high-activity pooled lot of cryopreserved hepatocytes are advised to minimize underpredictions of clearance.

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Section: Discussioncontrasting

confidence: 45%

Aldehyde Oxidase Activity in Donor-Matched Fresh and Cryopreserved Human Hepatocytes and Assessment of Variability in 75 Donors

et al. 2014

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“…MOCOS is therefore part of a complex pathway and the object of studies at different levels and expression studies associating the protein with genes involved in regulating transcription and apoptosis [31]. In wild silkworms, a MOCOS loss of function mutation was reported showing a mutant phenotype resulting in translucent skin [32].…”

Section: Resultsmentioning

confidence: 99%

A frameshift mutation in MOCOS is associated with familial renal syndrome (xanthinuria) in Tyrolean Grey cattle

Murgiano

Jagannathan

Piffer³

et al. 2016

BMC Vet Res

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BackgroundRenal syndromes are occasionally reported in domestic animals. Two identical twin Tyrolean Grey calves exhibited weight loss, skeletal abnormalities and delayed development associated with kidney abnormalities and formation of uroliths. These signs resembled inherited renal tubular dysplasia found in Japanese Black cattle which is associated with mutations in the claudin 16 gene. Despite demonstrating striking phenotypic similarities, no obvious presence of pathogenic variants of this candidate gene were found. Therefore further analysis was required to decipher the genetic etiology of the condition.ResultsThe family history of the cases suggested the possibility of an autosomal recessive inheritance. Homozygosity mapping combined with sequencing of the whole genome of one case detected two associated non-synonymous private coding variants: A homozygous missense variant in the uncharacterized KIAA2026 gene (g.39038055C > G; c.926C > G), located in a 15 Mb sized region of homozygosity on BTA 8; and a homozygous 1 bp deletion in the molybdenum cofactor sulfurase (MOCOS) gene (g.21222030delC; c.1881delG and c.1782delG), located in an 11 Mb region of homozygosity on BTA 24. Pathogenic variants in MOCOS have previously been associated with inherited metabolic syndromes and xanthinuria in different species including Japanese Black cattle. Genotyping of two additional clinically suspicious cases confirmed the association with the MOCOS variant, as both animals had a homozygous mutant genotype and did not show the variant KIAA2026 allele. The identified genomic deletion is predicted to be highly disruptive, creating a frameshift and premature termination of translation, resulting in severely truncated MOCOS proteins that lack two functionally essential domains. The variant MOCOS allele was absent from cattle of other breeds and approximately 4% carriers were detected among more than 1200 genotyped Tyrolean Grey cattle. Biochemical urolith analysis of one case revealed the presence of approximately 95% xanthine.ConclusionsThe identified MOCOS loss of function variant is highly likely to cause the renal syndrome in the affected animals. The results suggest that the phenotypic features of the renal syndrome were related to an early onset form of xanthinuria, which is highly likely to lead to the progressive defects. The identification of the candidate causative mutation thus enables selection against this pathogenic variant in Tyrolean Grey cattle.Electronic supplementary materialThe online version of this article (doi:10.1186/s12917-016-0904-4) contains supplementary material, which is available to authorized users.

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“…This, in combination with other studies (9,10), suggests that liver transplantation may induce postoperative VOD. Previous studies have revealed that the use of the immunosuppressant azathioprine following transplantation may damage the end of the small hepatic vein, the hepatic sinusoidal endothelial cells and the liver cells of the three zones of the hepatic lobules, causing multi-factorial abnormal pathophysiological processes, such as immune and inflammatory reactions and coagulation (11,12), leading to VOD. In the present case, the patient was treated with long-term tacrolimus following the liver transplantation, without any other drugs; we hypothesized that tacrolimus may have been the cause of the VOD.…”

Section: Discussionmentioning

confidence: 99%

A case of veno-occlusive disease following liver transplantation

Chen¹,

Wang²,

Fan³

et al. 2013

Experimental and Therapeutic Medicine

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The present case report describes the diagnosis and treatment of a patient with veno-occlusive disease (VOD) following liver transplantation. Combining the clinical data and relevant literature, the study aimed to consider the causes of VOD following liver transplantation, and the pathogenesis, clinical diagnosis and auxiliary examination features of VOD. A 42-year-old man who had a long history of taking traditional Chinese medicine (essential components unknown) underwent an orthotropic liver transplantation on January 14, 2011, due to small venous occlusion disease of the liver. The patient was treated with tacrolimus as an antirejection therapy following the surgery, and gradually developed right upper quadrant pain and fatigue. The examination results were consistent with the diagnostic standards for VOD. Following treatment with methylprednisolone, the patient was treated with alprostadil and Danhong injections. Forty days later, the patient’s total bilirubin (TBIL) level was observed to have decreased significantly, the liver function had returned to normal and the ascites had decreased, but had not completely disappeared. The patient then underwent a transjugular intrahepatic portosystemic shunt (TIPS) procedure, following which the ascites were shown to have completely disappeared.

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Polymorphism of Genes Involved in Purine Metabolism (XDH, AOX1, MOCOS) in Kidney Transplant Recipients Receiving Azathioprine

Cited by 31 publications

References 25 publications

Aldehyde Oxidase Activity in Donor-Matched Fresh and Cryopreserved Human Hepatocytes and Assessment of Variability in 75 Donors

Aldehyde Oxidase Activity in Donor-Matched Fresh and Cryopreserved Human Hepatocytes and Assessment of Variability in 75 Donors

A frameshift mutation in MOCOS is associated with familial renal syndrome (xanthinuria) in Tyrolean Grey cattle

A case of veno-occlusive disease following liver transplantation

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