Biochemistry- Proteins/Enzymology

Targeted Therapy for Inherited GPI Deficiency

Almeida, AM et al., 2007. N. Engl. J. Med. 356(16):1641-1647.

Abstract

Disrupted binding of the transcription factor Sp1 to the mutated promoter region of the mannosyl transferase-encoding gene PIGM causes inherited glycosylphosphatidylinositol (GPI) deficiency characterized by splanchnic vein thrombosis and epilepsy. We show that this results in histone hypoacetylation at the promoter of PIGM. The histone deacetylase inhibitor butyrate increases PIGM transcription and surface GPI expression in vitro as well as in vivo through enhanced histone acetylation in an Sp1-dependent manner. More important, the drug caused complete cessation of intractable seizures in a child with inherited GPI deficiency.

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Comment

An interest paper illustrating how genomics and epigenomics can be applied pediatric medicine not only to understand the basic genetic defect of a disease but also to devise a treatment which can alleviate some of the symptoms.

Nucleotide excision repair gene polymorphisms and recurrence after treatment for superficial bladder cancer.

Gu, J et al., 2005. Clin. Cancer Res. 11(4):1408-1415.

Abstract:

Purpose: Interindividual differences in DNA repair capacity not only modify individual susceptibility to carcinogenesis, but also affect individual response to cancer treatment. Nucleotide excision repair (NER) is one of the major DNA repair pathways in mammalian cells involved in the removal of a wide variety of DNA lesions. Polymorphisms in NER genes may influence DNA repair capacity and affect clinical outcome of bladder cancer treatment. Experimental Design: To test the influence of NER gene polymorphisms on superficial bladder cancer outcome (recurrence and progression), we conducted a follow-up study of 288 patients with superficial bladder cancer. Median follow-up among patients who were recurrence-free at the end of observation was 21.7 months from diagnosis. The specific polymorphic loci examined include XPA [A/G at 5' untranslated region (UTR)], XPC (poly AT, Ala499Val, Lys939Gln), XPD (Asp312Asn, Lys751Gln), XPG (His1104Asp), ERCC 1 (G/T at 3' UTR), and ERCC6 (Met1097Val, Arg1230Pro). Results: The ERCC6 (Met1097Val) polymorphism had a significant impact on recurrence: carriers of at least one variant allele (Val) had a significantly higher recurrence risk than carriers of the wild-type allele (Met/Met; hazard ratio, 1.54; 95% confidence interval, 1.02-2.33). There were no overall statistically significant differences in the distributions of the other polymorphisms between patients with and without recurrence. However, when we combined these variant genotypes, there was a significant trend for an increased recurrence risk with an increasing number of putative high-risk alleles. Using individuals with five or fewer putative high-risk alleles as the reference group, individuals with six to seven risk alleles and individuals with eight or more risk alleles had higher recurrence risks, with hazard ratios of 0.92 (0.54-1.57) and 2.53 (1.48-4.30), respectively (P for trend < 0.001). There was also a significant trend for shorter recurrence-free survival time with increasing number of variant alleles (log rank test, P = 0.0007). When we stratified the patients according to intravesical Bacillus Calmette-Guerin treatment, we found a significant trend for shorter recurrence-free survival time in patients with variant alleles of XPA or ERCC6 polymorphisms who received Bacillus Calmette-Guerin treatment (log rank test, P = 0.078 and 0.022, respectively). There were no significant individual or joint associations between these polymorphisms and progression. Conclusions: These data suggest that interindividual differences in DNA repair capacity may have an important impact on superficial bladder cancer recurrence. A pathway-based approach is preferred to study the effects of individual polymorphism on clinical outcomes

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Role of MTHFR genetic polymorphisms in the susceptibility to childhood acute lymphoblastic leukemia.

Krajinovic, M et al., 2004.  Blood 103(1):252-257.

The central role of methylenetetrahydrofolate reductase (MTHFR) in the folate metabolism renders MTHFR gene polymorphisms (C677T and A1298C) potential modulators of a variety of disorders whose development depends on folate/homocysteine imbalance. Here, we provide additional evidence on the protective role of these polymorphisms in acute lymphoblastic leukemia (ALL), the most common pediatric cancer. A case-control study was conducted in 270 ALL patients and 300 healthy controls of French-Canadian origin. The TT677/AA1298 and CC677/CC1298 individuals were associated with reduced risk of ALL (crude odds ratio [OR] = 0.4; 95% confidence interval [CI], 0.2-0.9; and OR = 0.3; 95% CI, 0.1-0.6; respectively). Further stratification in patients born before and after January 1996 (approximate time of Health Canada recommendation for folic acid supplement in pregnancy) revealed that the protective effect of MTHFR variants is accentuated and present only in children born before 1996. Similar results were obtained when a transmission disequilibrium test was performed on a subset of children (n = 95) in a family-based study. This finding suggests gene-environment interaction and its role in the susceptibility to childhood ALL, which is consistent with previous findings associating either folate deficiency or MTHFR polymorphisms with risk of leukemia

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Type II collagen gene variants and inherited osteonecrosis of the femoral head.

Liu, YF et al., 2005. N. Engl. J. Med. 352(22):2294-2301.

Abstract

BACKGROUND: Avascular necrosis of the femoral head (ANFH) causes disability that often requires surgical intervention. Most cases of ANFH are sporadic, but we identified three families in which there was autosomal dominant inheritance of the disease and mapped the chromosomal position of the gene to 12q13. METHODS: We carried out haplotype analysis in the families, selected candidate genes from the critical interval for ANFH on 12q13, and sequenced the promoter and exonic regions of the type II collagen gene (COL2A1) from persons with inherited and sporadic forms of ANFH. RESULTS: We identified a G-->A transition in exon 50 of COL2A1 in affected members of a four-generation family with ANFH. This transition predicts the replacement of glycine with serine at codon 1170 in a GXY repeat of type II collagen. Another pedigree was shown to harbor the same transition, but the mutant allele occurred on a different haplotype background. In a third family, a G-->A transition in exon 33 of the gene, causing a glycine-to-serine change at codon 717, was detected. No mutation was found in the COL2A1 coding region in sporadic cases of ANFH. CONCLUSIONS: All the patients with familial ANFH whom we studied carried COL2A1 mutations. In families with ANFH, haplotype and sequence analysis of the COL2A1 gene can be used to identify carriers of the mutant allele before the onset of clinical symptoms, allowing the initiation of measures that may delay progression of the disease.

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HIV reverse transcriptase structures: designing new inhibitors and understanding mechanisms of drug resistance.

Ren, J & Stammers, DK. 2005. Trends Pharmacol. Sci. 26(1):4-7.

Abstract

HIV reverse transcriptase (RT) is one of the main targets for the action of anti-AIDS drugs. The selection of drug-resistant HIV is a key problem in the continued treatment of the infection and thus new drugs are required. A significant body of information consisting of HIV-1 RT crystal structures with bound inhibitors has become available during the past several years, and, increasingly, such data will be of use in developing novel inhibitors. Two examples of crystal structures of HIV-1 RT with bound inhibitors have been published recently, one with the non-nucleoside CP94707 and the second with the nucleotide analogue drug tenofovir. Such structures will help the design of new drugs and improve our understanding of the mechanisms of resistance.

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Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and ?-glutamyl carboxylase) gene variants with warfarin sensitivity.

Shikata, E et al., 2004.  Blood 103(7):2630-2635

We analyzed mutations of 7 vitamin K--dependent protein and cytochrome P450 2C9 genes in 45 patients and investigated whether any contribute to the large interpatient variability in the warfarin dose-effect relationship. Total clearance and daily dose, INR and INR/Cp, were used as pharmacokinetic and pharmacodynamic indexes, respectively. Patients were grouped by genotype based on a single polymorphism and combinations of polymorphisms. Among the 30 sequence variants identified, CYP2C9*3, 165Thr --> Met of the factor II gene, -402G --> A, (37-bp repeat)n, and -746T --> C of the factor VII gene, and (CAA repeat)n of the ?-glutamyl carboxylase gene were selected as candidate polymorphisms. As the analysis of single polymorphisms implied, the highest INR/Cp mean values and the lowest warfarin maintenance doses were observed in patients homozygous for the 165Met, -402G, (37-bp repeat)6 and -746T alleles. Multiple regression analysis revealed that warfarin sensitivity was independently associated with -402G --> A, (CAA repeat)n, CYP2C9*3, and 165Thr --> Met, which accounted for 50% of variance. These results suggest that part of the considerable interpatient variation is attributable to genetic variation, and the combined genotyping of CYP2C9 and certain vitamin K--dependent protein genes is useful for predicting anticoagulant responses.

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Comment

One advantage of this research paper is its discussion of the various different gene products involved in blood coagulation.  It lays out how several different genes can each be polymorphic, producing individual enzymes with varying degrees of activity.  Thus, how one responds to a fixed dose of warfarin depends on one's constellation of enzymes that metabolize warfarin and those that recycle the oxidized/reduced forms of vitamin K.