Polymorphisms in Xenobiotic Metabolism Genes and Autism

Serajee, Fatema J.; Nabi, Rafiqun; Zhong, Hailang; Huq, A.H.M. Mahbubul

doi:10.1177/088307380401900603

Cited by 53 publications

(44 citation statements)

References 31 publications

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“…Interestingly enough, some of these genes code for factors involved in the antioxidant defense mechanism such as glutathione-Stransferase (GST M1) [12,95] an allele involved in the metabolism of glutathione, which is an intrinsic antioxidant, as well as differences in allele frequency for genes encoding reduced folate carrier [12] . Polymorphism for metal-responsive transcription factor (MTF-1) in autism [96], potentially alters expression of metallothionein and tissue levels of heavy metals such as mercury.…”

Section: Cerebellar Se In Autismmentioning

confidence: 99%

Oxidative Stress in Autism: Elevated Cerebellar 3-nitrotyrosine Levels

Sajdel-Sulkowska¹,

Lipiński²,

Windom³

et al. 2008

American J. of Biochemistry and Biotechnology

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It has been suggested that oxidative stress and/or mercury compounds play an important role in the pathophysiology of autism. This study compared for the first time the cerebellar levels of the oxidative stress marker 3-nitrotyrosine (3-NT), mercury (Hg) and the antioxidant selenium (Se) levels between control and autistic subjects. Tissue homogenates were prepared in the presence of protease inhibitors from the frozen cerebellar tissue of control (n=10; mean age, 15.5 years; mean PMI, 15.5 hours) and autistic (n=9; mean age 12.1 years; mean PMI, 19.3 hours) subjects. The concentration of cerebellar 3-NT, determined by ELISA, in controls ranged from 13.69 to 49.04 pmol g 1 of tissue; the concentration of 3-NT in autistic cases ranged from 3.91 to 333.03 pmol g 1 of tissue. Mean cerebellar 3-NT was elevated in autism by 68.9% and the increase was statistically significant (p=0.045). Cerebellar Hg, measured by atomic absorption spectrometry ranged from 0.9 to 35 pmol g 1 tissue in controls (n=10) and from 3.2 to 80.7 pmol g 1 tissue in autistic cases (n=9); the 68.2% increase in cerebellar Hg was not statistically significant. However, there was a positive correlation between cerebellar 3-NT and Hg levels (r=0.7961, p=0.0001). A small decrease in cerebellar Se levels in autism, measured by atomic absorption spectroscopy, was not statistically significant but was accompanied by a 42.9% reduction in the molar ratio of Se to Hg in the autistic cerebellum. While preliminary, the results of the present study add elevated oxidative stress markers in brain to the growing body of data reflecting greater oxidative stress in autism.

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Section: Cerebellar Se In Autismmentioning

confidence: 99%

Oxidative Stress in Autism: Elevated Cerebellar 3-nitrotyrosine Levels

Sajdel-Sulkowska¹,

Lipiński²,

Windom³

et al. 2008

American J. of Biochemistry and Biotechnology

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“…The proband was also heterozygous for two common polymorphisms of SLC40A1 : V221 (nt 663C→T) and ivs7 + 117C→T. The former allele (rs2304704) has been reported to occur in persons of various racial backgrounds with and without abnormal iron phenotypes [11,14,15,16,17]. The latter (rs7596205) has a reported allele frequency of 0.169 in Europeans, 0.044 in Asians and 0 in Africans [11].…”

Section: Resultsmentioning

confidence: 99%

<i>SLC40A1</i> c.1402G→A Results in Aberrant Splicing, Ferroportin Truncation after Glycine 330, and an Autosomal Dominant Hemochromatosis Phenotype

2007

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Background/Aims: To determine the molecular basis of a mild hemochromatosis phenotype in a man of Scottish-Irish descent. Methods: We sequenced genomic DNA to detect mutations of HFE, SLC40A1, TFR2, HAMP, and HFE2. RNA isolated from blood mononuclear cells was used to make cDNA. RT-PCR was performed to amplify ferroportin from cDNA, and amplified products were visualized by electrophoresis and sequenced. Results: The proband was heterozygous for the novel mutation c.1402G→A (predicted G468S) in exon 7 of the ferroportin gene (SLC40A1). Located in the last nucleotide before the splice junction, this mutation results in aberrant splicing to a cryptic upstream splice site located at nt 990 within the same exon. This causes truncation of ferroportin after glycine 330 and the addition of 4 irrelevant amino acids before terminating. The truncated ferroportin protein, missing its C-terminal 241 amino acids, would lack all structural motifs beyond transmembrane region 7. The patient was also heterozygous for the common HFE H63D polymorphism, but did not have coding region mutations in TFR2, HAMP, or HFE2. Conclusions: We conclude that this patient represents a unique example of hemochromatosis due to a single base-pair mutation of SLC40A1 that results in aberrant splicing and truncation of ferroportin.

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“…Paraoxonase 1 (PON1) , which is associated with organophosphate hydrolysis and plays a role in protection against the oxidative modifi cation of low-density lipoprotein, homocysteine-thiolactone, and bacterial endotoxins, has been implicated in autism (D'Amelio et al 2005 ;Herbert 2010 ;Pasca et al 2010 ;Serajee et al 2004 ). A signifi cant association of PON1 with autism was demonstrated in CaucasianAmerican ( p < 0.025), but not Italian, families in which less organophosphate is used (D'Amelio et al 2005 ).…”

Section: Paraoxigenase Genementioning

confidence: 95%

“…A familybased association study of 196 parent-proband trios using the transmission disequilibrium test (TDT) failed to demonstrate a signifi cant genetic association ( p = 1.00) (Serajee et al 2004 ). GSTP1 attracted attention for possessing potential teratogenic alleles, which might contribute to the phenotype of the affected child in the mother during pregnancy.…”

Section: Glutathione S-transferase Genementioning

confidence: 98%

“…The genes associated with this phenomena were allelic variations of genes related to the transsulfuration pathway and glutathione metabolism, such as glutathione S-transferase Mu 1 (GSTM1), glutathione S-transferase Pi 1 (GSTP1), and glutathione peroxidase (GPX1) (Buyske et al 2006 ;James et al 2006 ;Ming et al 2010 ;Serajee et al 2004 ).…”

Section: Genes From the Glutathione Pathwaymentioning

confidence: 99%

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