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  • 1
    Electronic Resource
    Electronic Resource
    Human leptin receptor gene in obese Japanese subjects: evidence against either obesity-causing mutations or association of sequence variants with obesity (1997)
    Springer
    Diabetologia 40 (1997), S. 1204-1210 
    Details
    ISSN: 1432-0428
    Keywords: Keywords Leptin ; leptin receptor ; Ob-R ; obesity ; sequence variant.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Leptin is an adipocyte-derived blood-borne satiety factor that acts on its cognate leptin receptor (Ob-R) in the hypothalamus, thereby regulating food intake and energy expenditure. To explore whether mutations in the Ob-R gene cause obesity in humans, we have searched for mutations in the gene for Ob-Rb, a biologically active receptor isoform, in obese Japanese subjects. We have also examined associations between such mutants and obesity in the Japanese. Genomic DNAs were used as templates in polymerase chain reaction (PCR) with primers selected to amplify exons 2 to 20 of the human Ob-Rb gene. Direct sequence analysis of the PCR products revealed 7 nucleotide sequence variants (Lys109Arg, Gln223Arg, Ser343Ser, Ser492Thr, Lys656Asn, Ala976Asp, and Pro1019Pro) in the Ob-Rb coding region from 17 obese Japanese subjects with a family history of obesity (BMI 39.3 ± 8.4 kg/m2). No missense and nonsense mutations were found such as those in Zucker fatty (fa/fa) rats and Koletsky (fa k /fa k) rats. Nucleotide substitutions occurred at relatively high frequencies at codons 109, 223, 976, and 1019 (79, 91, 100, and 85 %, respectively). Allele frequency of each variant determined by PCR-RFLP and PCR-single strand conformation polymorphism analyses showed no significant differences between 47 obese (BMI 35.1 ± 6.5 kg/m2) and 68 non-obese (BMI 21.6 ± 2.2 kg/m2) subjects. The present study represents the first report of sequence variants of the Ob-Rb gene in the Japanese and provides evidence against either obesity-causing mutations or association of sequence variants with obesity in obese Japanese subjects. [Diabetologia (1997) 40: 1204–1210]
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001250050808
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  • 2
    Electronic Resource
    Electronic Resource
    Thiamine-responsive lactic acidaemia: role of pyruvate dehydrogenase complex (1998)
    Springer
    European journal of pediatrics 157 (1998), S. 648-652 
    Details
    ISSN: 1432-1076
    Keywords: Key words Lactic acidaemia ; Thiamine ; Pyruvate dehydrogenase complex ; Thiamine pyrophosphate ; Sodium dichloroacetate
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Lactic acidaemia is sometimes associated with a defect of the pyruvate dehydrogenase complex (PDHC), catalysing the thiamine-dependent decarboxylation of pyruvate. The activity of PDHC for different thiamine pyrophosphate (TPP) concentrations was determined in 13 patients with lactic acidaemia, clinically responsive to thiamine treatment in order to assess the role of PDHC in the aetiology of thiamine-responsive lactic acidaemia. Culture of lymphoblastoid cells and skin fibroblasts and muscle biopsies were performed in these 13 patients. The activity of PDHC to sodium dichloroacetate (DCA), known as the activator of PDHC, was also examined. Three groups were identified according to PDHC activity. Group 1 (two patients) displayed very low PDHC activity, which was not increased by DCA. This PDHC activity increased at high TPP concentrations. Group 2 (five patients) displayed below normal PDHC activity at low TPP concentrations, increased by DCA. This PDHC activity became normal at high TPP concentrations. PDHC deficiency in these patients of groups 1 and 2 was due to a decreased affinity of PDHC for TPP. Group 3 included six patients with normal PDHC activity at low as well as high TPP concentrations. This PDHC activity was increased by DCA. Conclusion High concentrations of TPP may be required for maximal activity of PDHC in some patients with lactic acidaemia. The assay of PDHC activity, performed at a low concentration of TPP (1 × 10−4 mM) allows selection of patients with thiamine-responsive lactic acidaemia.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004310050903
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  • 3
    Electronic Resource
    Electronic Resource
    DNA diagnosis of pyruvate dehydrogenase deficiency in female patients with congenital lactic acidaemia (1995)
    Springer
    Journal of inherited metabolic disease 18 (1995), S. 534-546 
    Details
    ISSN: 1573-2665
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The diagnosis of pyruvate dehydrogenase (PDH) E1α deficiency, which is an X-linked inborn error of metabolism, is usually established by the measurement of PDH complex activity in cultured cells. However, heterozygous female patients with PDH E1α deficiency may be misdiagnosed when the normal X chromosome is predominantly expressed in the cultured cells. Therefore, in female patients with convincing clinical presentations of PDH E1α deficiency and the normal enzyme activity, the X-inactivation pattern should be analysed and the PDH E1α gene screened for mutations. For this screening, we applied the method of single-strand conformational polymorphism (SSCP) and DNA sequencing and examined 11 female patients with congenital lactic acidaemia whose PDH complex activity was normal in cultured cells. In 2 of the 11 female patients, we found distinct pathogenic missense mutations in the PDH E1α gene (G89S and G291R). Both affected patients showed a similar clinical presentation and had been diagnosed as West syndrome. In 3 of the 11 patients, we found a polymorphic base-pair substitution in exon 9 of the PDH E1α gene which resulted in a changed amino acid residue (M282L). We conclude that PCR-SSCP analysis of the PDH E1α gene, followed by DNA sequencing, is a useful method to screen for mutations of the PDH E1α gene in female patients with congenital lactic acidaemia who have normal enzyme activities in available samples, normal ratio of lactate to pyruvate, and predominantly raised lactate concentration in cerebrospinal fluid.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02435998
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  • 4
    Electronic Resource
    Electronic Resource
    Biochemical and molecular analysis of an X-linked case of Leigh syndrome associated with thiamin-responsive pyruvate dehydrogenase deficiency (1997)
    Springer
    Journal of inherited metabolic disease 20 (1997), S. 539-548 
    Details
    ISSN: 1573-2665
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We report molecular analysis of thiamin-responsive pyruvate dehydrogenase complex (PDHC) deficiency in a patient with an X-linked form of Leigh syndrome. PDHC activity in cultured lymphoblastoid cells of this patient and his asymptomatic mother were normal in the presence of a high thiamin pyrophosphate (TPP) concentration (0.4 mmol/L). However, in the presence of a low concentration (1 X 10-4 mmol/L) of TPP, the activity was significantly decreased, indicating that PDHC deficiency in this patient was due to decreased affinity of PDHC for TPP. The patient's older brother also was diagnosed as PDHC deficiency with Leigh syndrome, suggesting that PDHC deficiency in these two brothers was not a de novo mutation. Sequencing of the X-linked PDHC E1 α subunit revealed a C → G point mutation at nucleotide 787, resulting in a substitution of glycine for arginine 263. Restriction enzyme analysis of the E1α gene revealed that the mother was a heterozygote, indicating that thiamin-responsive PDHC deficiency associated with Leigh syndrome due to this mutation is transmitted by X-linked inheritance.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005305614374
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  • 5
    Electronic Resource
    Electronic Resource
    Molecular genetic analysis of a female patient with pyruvate dehydrogenase deficiency: detection of a new mutation and differential expression of mutant gene product in cultured cells (1995)
    Springer
    Journal of inherited metabolic disease 18 (1995), S. 547-557 
    Details
    ISSN: 1573-2665
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary A new 18 bp insertion mutation in the gene for the α subunit of pyruvate dehydrogenase (E1α) was found in a female patient with congenital lactic acidaemia. Cultured skin fibroblasts and Epstein—Barr virus-transformed lymphoblastoid cells from this patient showed decreased and normal pyruvate dehydrogenase complex (PDHC) activity, respectively. This 18 bp insertion was ade novo mutation, because it was not present in her parents. Although this female patient was heterozygous for the normal and the mutant alleles, 97% of cultured skin fibroblasts expressed the mutant allele, while 100% of cultured lymphoblastoid cells, 94% of peripheral blood lymphocytes and 98% of IL-2-activated T-cells expressed the normal allele. These results suggest that in this patient the X chromosome containing the normal allele was predominantly inactivated in fibroblasts and the X chromosome containing the mutant allele was predominantly inactivated in lymphocytes. The diagnosis of E1α deficiency is usually established by measurement of PDHC activity and the level of immunoreactive proteins. However, these methods are not sufficient to diagnose the disorder in female patients with E1α deficiency due to differential inactivation of the X chromosome. Therefore, it is necessary to develop a new method to firmly establish the diagnosis of E1α deficiency.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02435999
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