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1.
Molecular basis of dimethylglycine dehydrogenase deficiency associated with pathogenic variant H109R
Summary Dimethylglycine dehydrogenase (DMGDH) is a mitochondrial matrix flavoprotein that catalyses the demethylation of dimethylglycine
to form sarcosine, accompanied by the reduction of the covalently bound FAD cofactor. Electron-transfer flavoprotein reoxidizes
the reduced flavin and transfers reducing equivalents to the main mitochondrial respiratory chain through the enzyme ETF-ubiquinone
oxidoreductase. DMGDH plays a prominent role in choline and 1-carbon metabolism. We have expressed the mature form of human
DMGDH and the H109R variant identified in a DMGDH-deficient patient as N-terminally His6-tagged proteins in E. coli. The enzymes were purified to homogeneity by nickel affinity and anion exchange chromatography. The presence of FAD in the
wild-type enzyme was confirmed by spectrophotometric analysis. The H109R variant, however, had only 47% of the wild-type level
of bound flavin as expressed in E. coli, indicating its reduced affinity for FAD As previously described for rat enzyme studies, the wild-type human enzyme exhibited
two K
m values for N,N-dimethylglycine (K
m1 = 0.039 ± 0.010 mmol/L and Km2 = 15.4 ± 1.2 mmol/L). The addition of 4 μmol/L tetrahydrofolate resulted in a slight decrease in specific activity and a
substantial decrease in K
m2 (1.10 ± 0.55 mmol/L). The flavinated H109R variant protein exhibited a 27-fold decrease in specific activity and a 65-fold
increase in K
m, explaining its pathogenicity. Additionally, the current expression system represents a significant improvement over a previously
described rat DMGDH expression system and will enhance our ability to further study this important metabolic enzyme.
Competing interests: None declared
References to electronic databases: Dimethylglycine dehydrogenase: EC 1.5.99.2. Dimethylglycine dehydrogenase deficiency: OMIM 605850. Dimethylglycine oxidase
structure: PDB 1PJ5. 相似文献
2.
3.
Variants in the sulphonylurea receptor gene: association of the exon 16–3t variant with Type II diabetes mellitus in Dutch Caucasians 总被引:2,自引:0,他引:2
L. M. ’t Hart P. de Knijff J. M. Dekker R. P. Stolk G. Nijpels F. E. E. van der Does J. B. Ruige D. E. Grobbee R. J. Heine J. A. Maassen 《Diabetologia》1999,42(5):617-620
Aims/hypothesis. We have analysed to what extent two previously reported single nucleotide polymorphisms in the sulphonylurea receptor gene
(SUR1) are associated with Type II (non-insulin-dependent) diabetes mellitus in The Netherlands. Furthermore, we estimated haplotype
frequencies in control and diabetic populations, including data extracted from three other studies. Methods. Subjects with Type II diabetes (n = 388) and normoglycaemic subjects (n = 336) were randomly selected from two population-based studies, the Hoorn and Rotterdam
studies. DNA was typed for variants in exon 16 (-3c→t variant in the splice acceptor site) and exon 18 (Thr759Thr, ACC→ACT). Results. The genotype frequencies in both populations were similar. We observed an association of the exon 16–3t variant with Type II diabetes (allele frequencies 0.41 % vs 0.48 % in NGT and Type II diabetes, respectively, p = 0.01). There was no association between Type II diabetes and the variant in exon 18 or the combination of both variants
(p > 0.5). A strong linkage disequilibrium between the exon 16 and exon 18 variants was observed in the diabetic groups but
not, or less pronounced, in the control groups from the different studies. Haplotype estimation shows that several different
risk haplotypes exist in different Caucasian populations. Conclusion/interpretation. The exon 16–3t allele of the SUR1 gene is associated with Type II diabetes in the Netherlands. Based on estimated haplotype frequencies in different Caucasian
populations we conclude that multiple haplotypes on the SUR1 gene seem to confer a risk for developing Type II diabetes in Caucasians. [Diabetologia (1999) 42: 617–620]
Received: 6 November 1998 and in final revised form: 14 January 1999 相似文献
4.
Hart LM Dekker JM van Haeften TW Ruige JB Stehouwer CD Erkelens DW Heine RJ Maassen JA 《Diabetologia》2000,43(4):515-519
Abstract
Aims/hypothesis. The sulphonylurea receptor is a subunit of the ATP-sensitive potassium channel in the pancreatic beta cell. Mutations at
nt –3 of the splice acceptor site of exon 16 and a silent mutation in exon 18 of the gene for the sulphonylurea receptor (SUR1) associate with Type II (non-insulin-dependent) diabetes mellitus in several independent populations. We investigated whether
these gene variants associate with changes in the pattern of glucose-stimulated insulin secretion.?Methods. Subjects who had normal glucose tolerance (n = 67) and subjects with an impaired glucose tolerance (n = 94), originating from two independent studies, were included in the study. Beta-cell function and insulin sensitivity were
assessed by the hyperglycaemic clamp.?Results. Frequencies of the exon 16 –3t allele in the normal and impaired glucose tolerant groups were 46 % and 44 % respectively (p = NS). The more rare exon 18 T allele showed frequencies of 5 and 7 % respectively (p = NS). We observed an approximately 25 % reduced second-phase insulin secretion in carriers of the exon 16 –3t allele in both groups (p < 0.05). Estimates of insulin sensitivity did not show differences between carriers and non-carriers. The variant in exon
18 and the combined presence of variants in exon 16 and exon 18 were not associated with differences in insulin secretion
or insulin sensitivity in our study groups.?Conclusion/interpretation. The diabetes associated exon 16 –3t variant of the SUR1 gene associates with a functional change of the beta cell as reflected by reduced second-phase insulin secretion in response
to a standardized hyperglycaemia in normal and impaired glucose tolerant subjects. [Diabetologia (2000) 43: 515–519]
Received: 5 July 1999 and in revised form: 24 November 1999 相似文献
5.
The biochemistry, metabolism and inherited defects of the pentose phosphate pathway: A review 总被引:1,自引:0,他引:1
Summary The recent discovery of two defects (ribose-5-phosphate isomerase deficiency and transaldolase deficiency) in the reversible
part of the pentose phosphate pathway (PPP) has stimulated interest in this pathway. In this review we describe the functions
of the PPP, its relation to other pathways of carbohydrate metabolism and an overview of the metabolic defects in the reversible
part of the PPP.
Competing interests: None declared
Prof. Dr. Cornelis Jakobs was supervisor of this PhD project and Dr. Eduard A. Struys was co-supervisor
References to electronic databases: Transaldolase: EC 2.2.1.2. Ribose-5-phosphate isomerase: EC 5.3.1.6. Xylitol dehydrogenase: EC 1.1.1.9. Glucose-6-phosphate
dehydrogenase: EC 1.1.1.49. Transaldolase deficiency: OMIM #606003. Ribose-5-phosphate isomerase deficiency: OMIM #608611.
Pentosuria: %260800. Glucose-6-phosphate dehydrogenase deficiency OMIM +305900. TALDO1: GenBank # NM_006755. RPIA: GenBank # NM_144563.
相似文献
M. M. C. WamelinkEmail: |
6.
Maydan G Andresen BS Madsen PP Zeigler M Raas-Rothschild A Zlotogorski A Gutman A Korman SH 《Journal of inherited metabolic disease》2006,29(5):620-626
Summary Deficiency of the hepatic cytosolic enzyme tyrosine aminotransferase (TAT) causes marked hypertyrosinaemia leading to painful
palmoplantar hyperkeratoses, pseudodendritic keratitis and variable mental retardation (oculocutaneous tyrosinaemia type II
or Richner–Hanhart syndrome). Parents may therefore seek prenatal diagnosis, but this is not possible by biochemical assays
as tyrosine does not accumulate in amniotic fluid and TAT is not expressed in chorionic villi or amniocytes. Molecular analysis
is therefore the only possible approach for prenatal diagnosis and carrier detection. To this end, we sought TAT gene mutations in 9 tyrosinaemia II patients from three consanguineous Palestinian kindreds. In two kindreds (7 patients),
the only potential abnormality identified after sequencing all 12 exons and exon–intron boundaries was homozygosity for a
silent, single-nucleotide transversion c.1224G > T (p.T408T) at the last base of exon 11. This was predicted to disrupt the
5′ donor splice site of exon 11 and result in missplicing. However, as TAT is expressed exclusively in liver, patient mRNA could not be obtained for splicing analysis. A minigene approach was therefore
used to assess the effect of c.1224G > T on exon 11 splicing. Transfection experiments with wild-type and c.1224G > T mutant
minigene constructs demonstrated that c.1224G > T results in complete exon 11 skipping, illustrating the utility of this approach
for confirming a putative splicing defect when cDNA is unavailable. Homozygosity for a c.1249C > T (R417X) exon 12 nonsense
mutation (previously reported in a French patient) was identified in both patients from the third kindred, enabling successful
prenatal diagnosis of an unaffected fetus using chorionic villous tissue.
Competing interests: None declared
References to electronic databases: tyrosinaemia type II (OMIM +276600); hepatic cytosolic tyrosine aminotransferase (EC 2.6.1.5);
GenBank: accession number for TAT mRNA, NM_000353; accession number for TAT genomic DNA, NC_000016. 相似文献
7.
8.
N. Kyprianou E. Murphy P. Lee I. Hargreaves 《Journal of inherited metabolic disease》2009,32(2):289-296
Summary Phenylketonuria (PKU) is an autosomal recessive disorder resulting in neurological and intellectual disability when untreated.
However, even in treated patients there may be residual neurological impairment such as tremor. It has been suggested that
the hyperphenylalaninaemia in patients with PKU reduces complex I (NADH:ubiquinone reductase) activity of the mitochondrial
respiratory chain (MRC) and/or biosynthesis of coenzyme Q10 (CoQ10), which acts as an electron carrier in the MRC, leading to impaired energy metabolism in the brain of patients with PKU and
hence the neurological pathology. The aim of this study was to elucidate the mechanism of phenylalanine (Phe) toxicity on
the MRC. We compared mean plasma and blood-spot Phe and mononuclear CoQ10 levels in 17 patients with PKU and a tremor compared to 22 patients without tremor. Human 1321N1 astrocytoma cells were exposed
to hyperphenylalaninaemia by the addition of 300 or 900 μmol/L of Phe to the cell culture medium. Following 96 h of culture
we measured complex I and citrate synthase activities and CoQ10 level. Results showed no significant difference in Phe or CoQ10 levels in patients with tremor compared to those without tremor. Further, hyperphenylalaninaemia did not cause a significant
reduction in complex I activity or CoQ10 biosynthesis, even when taking into account the mitochondrial enrichment of the cell samples by expressing complex I and
CoQ10 as a ratio to citrate synthase. In conclusion, the results of this study suggest that hyperphenylalaninaemia does not contribute
to the pathophysiology of PKU by causing a decrease in MRC complex I activity and/or CoQ10 biosynthesis.
Competing interests: None declared
References to electronic databases: Phenylketonuria: PKU. OMIM 261600. Citrate synthase: EC 4.1.3.7. Cytochrome oxidase: EC 1.9.3.1. Succinate:cytochrome-c oxidoreductase: EC 1.3.5.1 + EC 1.10.2.2. NADH:cytochrome-c oxidoreductase: EC 1.6.5.3 + EC 1.10.2.2. Hydroxymethylglutaryl-CoA reductase: EC 1.1.1.98. Ubiquinol:cytochrome-c oxidoreductase: EC 1.10.2.2. Succinate:ubiquinone reductase: EC 1.3.5.1. NADH:ubiquinone reductase: EC 1.6.5.3. Phenylalanine
hydroxylase: EC 1.14.16.1. 相似文献
9.
10.
V. Valayannopoulos L. Hubert J. F. Benoist S. Romano J. B. Arnoux D. Chrétien J. Kaplan F. Fakhouri D. Rabier A. Rötig A. S. Lebre A. Munnich Y. de Keyzer P. de Lonlay 《Journal of inherited metabolic disease》2009,32(2):159-162
Summary An adult patient with methylmalonic aciduria due to defective cobalamin synthesis (CblA) responsive to vitamin B12 presented suddenly with severe visual impairment ascribed to optic atrophy followed by a fatal multiorgan failure and lactic
acidosis but low methylmalonic acid in plasma and urine. Multiple deficiency of oxidative phosphorylation was found in the
patient’s liver. We suggest that patients with B12-sensitive methylmalonic aciduria who have a milder clinical course should be carefully monitored for long-term complications.
Competing interests: None declared
References to electronic databases: Methylmalonic aciduria (MMA): OMIM 251000, 277400, 251100 (CblA), 277410 (CblD), 251110 (CblB), 277380, 606169. Adenosylcobalamin:
EC 2.7.7.62. Methylmalonyl-coenzyme A mutase (MUT): EC 5.4.99.2. Citrate synthase: EC 2.3.3.1. Succinate-CoA ligase (GDP-forming):
EC 6.2.1.4. Succinate-CoA ligase (ADP-forming): EC 6.2.1.5. Succinate dehydrogenase (ubiquinone): EC 1.3.5.1. Fumarate hydratase:
EC 4.2.1.2. ATP citrate synthetase: EC 2.3.3.8. Pyruvate dehydrogenase: EC 1.2.4.1. Pyruvate carboxylase: EC 6.4.1.1. Nucleoside-diphosphate
kinase: EC 2.7.4.6.
Presented at the Annual Symposium of the SSIEM, Lisbon, Portugal, 2–5 September 2008. 相似文献
11.
12.
S. C. Lim J. J. Liu H. Q. Low N. G. Morgenthaler Y. Li L. Y. Yeoh Y. S. Wu S. K. Goh C. Y. Chionh S. H. Tan Y. C. Kon P. C. Soon Y. M. Bee T. Subramaniam C. F. Sum K. S. Chia 《Diabetologia》2009,52(7):1343-1351
Aims/hypothesis Evolving research suggests that common and rare alleles jointly constitute the genetic landscape of complex disease. We studied
the association between 43 pathway-related candidate genes with ‘intermediate phenotype’ (i.e. corresponding plasma protein)
and diabetic nephropathy in a customised microarray of 1,536 SNPs.
Methods In this case–control study of type 2 diabetic Chinese individuals with and without diabetic nephropathy, cases (n = 545) were defined on the basis of a spot urinary albumin/creatinine ratio (ACR) > 113 mg/mmol; the value for controls (n = 503) was ACR < 3.3 mg/mmol. Genotyping was performed using Illumina GoldenGate assay.
Results No single nucleotide polymorphism (SNP) remained significant in single locus analysis after correction for multiple testing.
Therefore, we explored the best ∼1% SNPs. Of these 13 SNPs, four clustered to a 5′ end NADPH oxidase homologue 4 (NOX4) haplotype (GGCC frequency = 0.776) with estimated OR for diabetic nephropathy of 2.05 (95% CI 1.04–4.06) (heterozygous)
and 2.48 (1.27–4.83) (homozygous) (p = 0.0055). The haplotype was correlated with plasma Cu/Zn superoxide dismutase (SOD) concentration, suggesting increased
oxidative burden. Endothelin-1 SNP (rs1476046G>A, frequency = 0.252) was correlated with plasma C-terminal pro-endothelin-1
concentrations with an estimated OR for diabetic nephropathy of (heterozygous) 1.26 (0.96–1.66) and (homozygous) 1.87 (1.13–3.12)
(p = 0.0072). Nitric oxide synthase 1 (NOS1) 5′ haplotype (TGTC frequency = 0.38) also revealed a suggestive association with diabetic nephropathy: heterozygous 1.26
(0.95–1.67), homozygous 1.57 (1.04–2.35) (p = 0.0073). A rare NADPH oxidase homologue 1 (NOX1)-coding non-synonymous SNP (Arg315His, frequency = 0.006) was found exclusively among cases.
Conclusions/interpretation Our preliminary observations suggest that common haplotypes from NOX4 and endothelin-1 SNP correlated with plasma Cu/Zn SOD and C-terminal pro-endothelin-1 concentrations, respectively, and might
have conferred diabetic nephropathy susceptibility. Common NOS1 and rare NOX1 variants also revealed a suggestive association with diabetic nephropathy. Future studies to validate our observation are
needed.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorised users. 相似文献
13.
Chistiakov DA Potapov VA Khodirev DC Shamkhalova MS Shestakova MV Nosikov VV 《Acta diabetologica》2009,46(1):43-49
The KCNJ11 and ABCC8 genes encode the components of the pancreatic ATP-sensitive potassium (KATP) channel, which regulates
insulin secretion by β-cells and hence could be involved in the pathogenesis of type 2 diabetes (T2D). The KCNJ11 E23K and
ABCC8 exon 31 variants have been studied in 127 Russian T2D patients and 117 controls using the polymerase chain reaction-restriction
fragment length polymorphism (PCR-RFLP) approach. The KCNJ11 E23 variant and the ABCC8 exon 31 allele A were associated with
higher risk of T2D [Odds ratio (OR) of 1.53 (P = 0.023) and 2.41 (P = 1.95 × 10−5)], respectively. Diabetic carriers of the ABCC8 G/G variant had reduced 2 h glucose compared to A/A + A/G (P = 0.031). The G/G genotype of ABCC8 was also significantly associated with increased both fasting and 2 h serum insulin in
diabetic and non-diabetic patients. A HOMA-β value characterizing the β-cell homeostasis was higher in the non-diabetic carriers
homozygous for G/G (98.0 ± 46.9) then for other genotypes (HOMA-β = 85.6 ± 45.5 for A/A + A/G, P = 0.0015). The KCNJ11 E23K and ABCC8 exon 31 variants contribute to susceptibility to T2D diabetes, glucose intolerance and
altered insulin secretion in a Russian population. 相似文献
14.
Possible involvement of NADPH oxidase and JNK in homocysteine-induced oxidative stress and apoptosis in human umbilical vein endothelial cells 总被引:4,自引:0,他引:4
Hyperhomocysteinemia is an independent risk factor for cardiovascular diseases, although the mechanism leading to vascular
dysfunction is not clear. The aim of this study was to examine the effect of homocysteine (Hcy) on oxidative stress and apoptosis
in human umbilical vein endothelial cells (HUVECs). HUVECs were challenged for 24 h with Hcy (10 μM-3 mM) in the presence of various stress signaling inhibitors, including the nicotinamide adenine dinucleotide phosphate (NADPH)
oxidase inhibitor apocynin (100 μM), the p38 mitogen-activated protein kinase inhibitor SB203580 (2.5 μM), the extracellular signal-regulated kinase inhibitor U0126 (2.5 μM), the stress-activated protein kinase (SAPK)/c-Jun NH2-terminal kinase (JNK) inhibitor JNK inhibitor II (10 μM), and antioxidants α-tocopherol (5 μg/mL) and N-acetyl cysteine (NAC, 2 mM). Reactive oxygen species (ROS) were detected using 5-(6)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate. Apoptosis
was evaluated by 4′,6′-diamidino-2′-phenylindoladihydrochloride staining, annexin-V phosphatidyl-serine/propidium iodide,
and caspase-3 assay. NADPH oxidase and SAPK/JNK signal were evaluated with immunoblotting. Hcy significantly enhanced ROS
generation and apoptosis after 24-h incubation. Apocynin prevented Hcy-induced ROS generation but only partially restored
Hcy-induced apoptosis. JNK inhibitor II, α-tocopherol, and NAC partially reduced Hcy-induced apoptosis, although SB203580
and U0126 had no effect. Immunoblotting analysis confirmed upregulation of NADPH oxidase and SAPK/JNK signaling. Collectively,
our results suggested that Hcy may induce oxidative stress and apoptosis through an NADPH oxidase and/or JNK-dependent mechanisms(s).
The first two authors contributed equally to this work. 相似文献
15.
Characterization of an apparently synonymous F5 mutation causing aberrant splicing and factor V deficiency 下载免费PDF全文
F. Nuzzo C. Bulato B. I. Nielsen K. Lee S. J. Wielders P. Simioni N. S. Key E. Castoldi 《Haemophilia》2015,21(2):241-248
Coagulation factor V (FV) deficiency is a rare autosomal recessive bleeding disorder. We investigated a patient with severe FV deficiency (FV:C < 3%) and moderate bleeding symptoms. Thrombin generation experiments showed residual FV expression in the patient's plasma, which was quantified as 0.7 ± 0.3% by a sensitive prothrombinase‐based assay. F5 gene sequencing identified a novel missense mutation in exon 4 (c.578G>C, p.Cys193Ser), predicting the abolition of a conserved disulphide bridge, and an apparently synonymous variant in exon 8 (c.1281C>G). The observation that half of the patient's F5 mRNA lacked the last 18 nucleotides of exon 8 prompted us to re‐evaluate the c.1281C>G variant for its possible effects on splicing. Bioinformatics sequence analysis predicted that this transversion would activate a cryptic donor splice site and abolish an exonic splicing enhancer. Characterization in a F5 minigene model confirmed that the c.1281C>G variant was responsible for the patient's splicing defect, which could be partially corrected by a mutation‐specific morpholino antisense oligonucleotide. The aberrantly spliced F5 mRNA, whose stability was similar to that of the normal mRNA, encoded a putative FV mutant lacking amino acids 427–432. Expression in COS‐1 cells indicated that the mutant protein is poorly secreted and not functional. In conclusion, the c.1281C>G mutation, which was predicted to be translationally silent and hence neutral, causes FV deficiency by impairing pre‐mRNA splicing. This finding underscores the importance of cDNA analysis for the correct assessment of exonic mutations. 相似文献
16.
Andréa G. K. Ferreira Daniela D. Lima Débora Delwing Vanize Mackedanz Bárbara Tagliari Janaína Kolling Patrícia F. Schuck Moacir Wajner Angela T. S. Wyse 《Metabolic brain disease》2010,25(2):161-168
In the present study we investigated the effect of acute hyperprolinemia on some parameters of energy metabolism, including
the activities of succinate dehydrogenase and cytocrome c oxidase and 14CO2 production from glucose and acetate in cerebral cortex of young rats. Lipid peroxidation determined by the levels of thiobarbituric
acid-reactive substances, as well as the influence of the antioxidants α-tocopherol plus ascorbic acid on the effects elicited
by Pro on enzyme activities and on the lipid peroxidation were also evaluated. Wistar rats of 12 and 29 days of life received
one subcutaneous injection of saline or proline (12.8 or 18.2 μmol/g body weight, respectively) and were sacrificed 1 h later.
In another set of experiments, 5- and 22-day-old rats were pretreated for a week with daily intraperitoneal administration
of α-tocopherol (40 mg/kg) plus ascorbic acid (100 mg/kg) or saline. Twelve hours after the last injection, rats received
one injection of proline or saline and were sacrificed 1 h later. Results showed that acute administration of proline significantly
reduced cytochrome c oxidase activity and increased succinate dehydrogenase activity and 14CO2 production in cerebral cortex, suggesting that Pro might disrupt energy metabolism in brain of young rats. In addition, proline
administration increased the thiobarbituric acid-reactive substances levels, which were prevented by antioxidants. These findings
suggest that mitochondrial dysfunction and oxidative stress may be important contributors to the neurological dysfunction
observed in some hyperprolinemic patients and that treatment with antioxidants may be beneficial in this pathology. 相似文献
17.
18.
Sass JO Walter M Shield JP Atherton AM Garg U Scott D Woods CG Smith LD 《Journal of inherited metabolic disease》2012,35(3):437-442
3-hydroxyisobutyric aciduria is an organic aciduria with a poorly understood biochemical basis. It has previously been assumed
that deficiency of 3-hydroxyisobutyrate dehydrogenase (HIBADH) in the valine catabolic pathway is the underlying enzyme defect,
but more recent evidence makes it likely that individuals with 3-hydroxyisobutyryic aciduria represent a heterogeneous group
with different underlying mechanisms, including respiratory chain defects or deficiency of methylmalonate semialdehyde dehydrogenase.
However, to date methylmalonate semialdehyde dehydrogenase deficiency has only been demonstrated at the gene level for a single
individual. We present two unrelated patients who presented with developmental delay and increased urinary concentrations
of 3-hydroxyisobutyric acid. Both children were products of consanguineous unions and were of European or Pakistani descent.
One patient developed a febrile illness and subsequently died from a hepatoencephalopathy at 2 years of age. Further studies
were initiated and included tests of the HIBADH enzyme in fibroblast homogenates, which yielded normal activities. Sequencing
of the ALDH6A1 gene (encoding methylmalonate semialdehyde dehydrogenase) suggested homozygosity for the missense mutation c.785 C > A (S262Y)
in exon 7 which was not found in 210 control alleles. Mutation analysis of the ALDH6A1 gene of the second patient confirmed the presence of a different missense mutation, c.184 C > T (P62S), which was also identified
in 1/530 control chromosomes. Both mutations affect highly evolutionarily conserved amino acids of the methylmalonate semialdehyde
dehydrogenase protein. Mutation analysis in the ALDH6A1 gene can reveal a cause of 3-hydroxyisobutyric aciduria, which may present with only slightly increased urinary levels of
3-hydroxyisobutyric acid, if a patient is metabolically stable. 相似文献
19.
Kölker S Sauer SW Hoffmann GF Müller I Morath MA Okun JG 《Journal of inherited metabolic disease》2008,31(2):194-204
Summary Inherited disorders of amino and organic acid metabolism have a high cumulative frequency, and despite heterogeneous aetiology
and varying clinical presentation, the manifestation of neurological disease is common. It has been demonstrated for some
of these diseases that accumulating pathological metabolites are directly involved in the manifestation of neurological disease.
Various pathomechanisms have been suggested in different in vitro and in vivo models including an impairment of brain energy metabolism, an imbalance of excitatory and inhibitory neurotransmission, altered
transport across the blood–brain barrier and between glial cells and neurons, impairment of myelination and disturbed neuronal
efflux of metabolic water. This review summarizes recent knowledge on pathomechanisms involved in phenylketonuria, glutaric
aciduria type I, succinic semialdehyde dehydrogenase deficiency and aspartoacylase deficiency with examples, highlighting
general as well as disease-specific concepts and their putative impact on treatment.
Competing interests: None declared
References to electronic databases: Phenylketonuria: OMIM #261600. Glutaric aciduria type I: OMIM #231670. Succinic semialdehyde dehydrogenase deficiency: OMIM
#271980. Aspartoacylase disease (Canavan–van Bogaert–Bertrand disease): OMIM #271900. Phenylalanine hydroxylase: EC 1.14.16.1.
Glutaryl-CoA dehydrogenase: EC 1.3.99.7. Succinic semialdehyde dehydrogenase: EC 1.2.1.16. Aspartoacylase: EC 3.5.1.15.
Presented at the Annual Symposium of the SSIEM, Hamburg, 4–7 September 2007 相似文献
20.
Novel NF1 gene mutation in a Japanese patient with neurofibromatosis type 1 and a gastrointestinal stromal tumor 总被引:1,自引:0,他引:1
Nemoto H Tate G Schirinzi A Suzuki T Sasaya S Yoshizawa Y Midorikawa T Mitsuya T Dallapiccola B Sanada Y 《Journal of gastroenterology》2006,41(4):378-382
Many mutations of the NF1 gene have been reported in patients with neurofibromatosis type 1 (NF1); however, there have been no documented NF1 gene mutations in Japanese NF1 patients. In the present study, we used the polymerase chain reaction (PCR) and DNA sequencing
analysis to characterize the NF1 gene in a 53-year-old Japanese patient with NF1 who suffered from neurofibroma, pheochromocytoma, and gastrointestinal stromal
tumor (GIST). Direct sequence analyses revealed a single base substitution in the splicing donor site of intron 6 (IVS6 888+1,
G → A) in one NF1 allele, resulting in an altered splice site (ss) in the mutated allele. Splicing at the cryptic 5′ ss in the mutated allele
generated mRNA with an insertion of 60 nucleotides. In addition, we screened for mutations in exons 9, 11, 13, and 17 of the
c-kit gene in GIST and the succinate dehydrogenase subunit D (SDHD) gene in the pheochromocytoma, but we did not detect any somatic mutations. We report here the first case of an NF1 patient
with four neoplasms: neurofibroma, pheochromocytoma, astrocytoma and GIST. Our results suggest that the molecular pathogenesis
of GISTs in NF1 patients is different from that in non-NF1 patients. 相似文献