Sub-Areas to Mn-SOD2:
Association with Schizophrenia
(2)
Association with Parkinson
(1)
(Journal Article): Manganese Superoxide Dismutase Alanine to Valine Polymorphism and Risk of Neuropathy and Nephropathy in Egyptian Type 1 Diabetic Patients
El Masry TM, Abou Zahra MA, El Tawil MM, Khalifa RA (Department of Clinical Pathology, Ain Shams University Hospital, Cairo, Egypt,
tarek_msry(at)yahoo.com
)
IN:
Rev Diabetic Stud
2005; 2(2):70-74
Impact Factor(s) of Rev Diabetic Stud: 0.125 (2006)
ABSTRACT: Oxidative stress, characterized by a marked increase in the level of oxygen free radicals (OFR), has been implicated in the development of diabetic microangiopathic complications, such as diabetic neuropathy (DN) and nephropathy (DP). Antioxidant enzymes may protect against the rapid onset and progression of microangiopathy, by reducing the excess of OFR and peroxides. Mutations and polymorphisms in genes encoding such enzymes may therefore result in a predisposition to this disorder. AIM: we investigated the role of genes encoding the antioxidant enzyme, mitochondrial superoxide dismutase (Mn-SOD2), in DN and DP pathogenesis in an Egyptian population. We studied Ala(-9)Val polymorphism of the Mn-SOD2 gene in type 1 diabetic patients (n = 65) with DN (n = 40) or DP (n = 45). METHODS: we used polymerase chain reaction (PCR) assays with restriction fragment length polymorphism for rapid detection of polymorphisms. These assays involved the use of mismatch PCR primers to create restriction sites in the amplified product only in presence of the polymorphic base. The PCR product was then digested with AgeI restriction enzyme to detect Ala(-9)Val polymorphic sites. RESULTS: the frequencies of the Ala allele (odds ratio (OR) = 0.438, 95% CI of 0.247 - 0.778) and the Ala/Ala genotype (OR = 0.26, 95% CI of 1.39 - 10.266) were significantly lower in diabetic neuropathy patients. In contrast, the frequencies of the Val allele (OR = 2.282, 95% CI of 1.286 - 4.05) and the homozygous Val/Val genotype (OR = 6.68, 95% CI of 0.3 - 0.76) were significantly higher in patients with DN than diabetics without neuropathy. Although the Val allele was more frequently detected in DP patients than diabetics without nephropathy (OR = 3.2), this difference was statistically non-significant. In conclusion, Ala(-9)Val substitution in the Mn-SOD2 gene was associated with DN in Egyptian diabetic children but not a significant factor in diabetic patients with nephropathy.
TYPE OF PUBLICATION: Original article
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(Journal Article): On signal sequence polymorphisms and diseases of distribution.
Rosenblum JS, Gilula NB, Lerner RA (Department of Chemistry, Scripps Research Institute, La Jolla, CA 92037, USA.)
IN:
Proc Natl Acad Sci U S A
1996; 93(9):4471-4473
Impact Factor(s) of Proc Natl Acad Sci U S A: 10.452 (2004), 10.272 (2003), 10.7 (2002), 10.896 (2001)
ABSTRACT: We report a previously unappreciated property of the signals that target organelle-specific proteins to their subcellular sites of action. Such targeting sequences are shown to be polymorphic. We discovered this polymorphism when we cloned the mitochondrial manganese-containing superoxide dismutase from cell lines of normal individuals and patients with genetic diseases of premature aging and compared their sequences to each other and to those previously reported. The polymorphism consists of a single nucleotide change in the region of the DNA that encodes the signal sequence such that either an alanine or valine is present. Subsequently, eight cell lines were analyzed and all three possible combinations of the two signal sequences were observed. Such signal sequence polymorphisms could result in diseases of distribution, where essential proteins are not properly targeted, thereby leading to absolute or relative deficiencies of critical enzymes within specific cellular compartments. Progeria and related syndromes may be diseases of distribution.
TYPE OF PUBLICATION: Original article
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(Journal Article): Polymorphisms in the Mn-SOD and EC-SOD genes and their relationship to diabetic neuropathy in type 1 diabetes mellitus.
Chistyakov DA, Savost'anov KV, Zotova EV, Nosikov VV (INSERM U36, College de France, 75231 Paris Cedex 05, France.,
dimitry.chistiakov@eudoramail.com
)
IN:
BMC Med Genet
2001; 2:4
ABSTRACT: BACKGROUND: Oxidative stress, resulting in a marked increase in the level of oxygen free radicals (OFR), has been implicated in the etiology of diabetic neuropathy (DN). Antioxidant enzymes may protect against the rapid onset and progression of DN, by reducing the excess of OFR and peroxide. Mutations and polymorphisms in the genes encoding such enzymes may therefore result in predisposition to DN. We investigated the role of genes encoding two antioxidant enzymes, mitochondrial (Mn-SOD) and extracellular (EC-SOD) superoxide dismutase, in DN pathogenesis in a Russian population. We studied Ala(-9)Val and Ile58Thr polymorphisms of the Mn-SOD gene and Arg213Gly dimorphism of the EC-SOD gene in type 1 diabetic patients with (n = 82) and without DN (n = 84). RESULTS: We developed and used a new polymerase chain reaction (PCR) assays for rapid detection of polymorphisms. These assays involved the use of mismatch PCR primers to create restriction sites in the amplified product only in presence of the polymorphic base. The PCR product was than digested with BshTI, Eco32I or Eco52I to detect Ala(-9)Val, Ile58Thr or Arg213Gly polymorphic site respectively. The frequencies of the Ala allele (50.6% vs. 68.5%, p < 0.002) and the Ala/Ala genotype (17.1% vs. 39.3%, p < 0.005) of the Mn-SOD gene were significantly lower in DN patients than in diabetic subjects without DN. In contrast, the Val allele (49.4% vs. 31.5%, p < 0.002) and the Val/Val genotype (15.9% vs. 2.4%, p < 0.01) were significantly more frequent in the DN patients than in the control group. CONCLUSIONS: Ala(-9)Val substitution in the Mn-SOD gene was associated with DN in a Russian population
TYPE OF PUBLICATION: Original article
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(Journal Article): Predisposing genetic factors for diabetic polyneuropathy in patients with type 1 diabetes: a population-based case-control study.
Strokov IA, Bursa TR, Drepa OI, Zotova EV, Nosikov VV, Ametov AS (Department of Neurology, I. M. Sechenov Medical Academy, Moscow, Russia.)
IN:
Acta Diabetol
2003; 40(Suppl 2):S375-379
Impact Factor(s) of Acta Diabetol: 0.335 (2004), 0.811 (2003), 0.647 (2002), 0.817 (2001)
ABSTRACT: Oxidative stress plays a key role in the development of microvascular complications of diabetes mellitus (DM). Antioxidant enzymes protect against the rapid onset of diabetic polyneuropathy (DPN) by reducing oxidative stress. Genetic variations that affect activity or expression levels of the antioxidant enzymes may therefore be associated with susceptibility to DPN. We examined polymorphic markers Ala(-9)Val in SOD2 gene and Arg213Gly in SOD3 gene for possible relation to DPN in Russian type 1 diabetic patients. Four hundred Russian white patients with type 1 diabetes were studied using neurological examination according to recommendations of the San Antonio Conference on Diabetic Neuropathy. Two groups were formed from the general sample. Definition of frequency distribution of the polymorphic markers was performed in these groups using the polymerase chain reaction. Genes encoding the enzymes Mn-SOD and extracellular superoxide dismutase (EC-SOD) were found to be associated with the pathogenesis of DPN.
TYPE OF PUBLICATION: Original article
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(Journal Article): Genomics of type I diabetes mellitus and its late complications.
Nosikov VV
IN:
Mol Biol (Mosk)
2004; 38(1):150-164
ABSTRACT: In ethnic Russians, MHC (HLA) was shown to be the major locus determining the predisposition to type 1 diabetes mellitus (T1DM). To map the regions linked to T1DM, families with concordant or discordant sib pairs were selected from the Russian population of Moscow. With these families, linkage to T1DM was demonstrated for CTLA4 (IDDM12, 2q32.1-q33), which codes for a T-cell surface antigen, and PDCD2 (IDDM8, 6q25-q27), which is homologous to the mouse programmed cell death activator gene. With polymorphic microsatellites, regions 3q21-q25 (IDDM9) and 10p12.2 (IDDM10) were also linked to T1DM. Case/control and family studies of the polymorphic markers from region 11p13 revealed a new T1DM-associated locus in the vicinity of the catalase gene (CAT); linkage to this locus was not reported earlier for other populations. Diabetic polyneuropathy (DPN) proved to be associated with single-nucleotide polymorphisms Ala(-9)Val (SOD2), Arg213Gly (SOD3), and T(-262)C (CAT) and with a polymorphic microsatellite of the NOS2 promoter. Hence oxidative stress, which results from hyperglycemia, increased mitochondrial production of superoxide radicals, and insufficient activities of antioxidative enzymes, was assumed to play an important part in DPN development in T1DM. Diabetic nephropathy (DN) showed no association with the antioxidative enzyme genes. However, the association was observed for the insertion/deletion (I/D) polymorphism of ACE and the ecNOS34a/4b polymorphism of NOS3, two genes involved in controlling vascular tonicity, and for the I/D polymorphism of APOB and the epsilon 2/epsilon 3/epsilon 4 polymorphism of APOE, two genes involved in lipid transport. In addition, polymorphic microsatellites of chromosome 3q21-q25 proved to be closely associated with DN. The tightest association was established for D3S1550, carriers of allele 12 or genotype 12/14 having high risk of DN (OR = 4.85 and 6.25, respectively). Region 3q21-q25 was assumed to contain a major gene determining DN development, while the other DN-associated genes mostly affect the progression of DN.
TYPE OF PUBLICATION: Review
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