Regular Article
Retarded and Aberrant Splicings Caused by Single Exon Mutation in a Phosphoglycerate Kinase Variant

https://doi.org/10.1006/abbi.1996.0089Get rights and content

Abstract

The molecular abnormality of a phosphoglycerate kinase variant which was associated with severe tissue enzyme deficiency and episodes of muscle contractions and myoglobinuria was examined. Analysis of the patient's DNA showed the existence of a nucleotide transversion A/T → C/G in exon 7. No other nucleotide change was detected in the coding region of the variant gene. The mutation should produce a single amino acid substitution Glu → Ala at protein position 251 counting from the NH2-terminal acetyl serine residue. The protein abnormality caused by the amino acid substitution cannot explain the enzyme deficiency. Northern blot hybridization indicated that the PGK mRNA content of the patient's lymphoblastoid cells was only about 10% of that of normal. Nucleotide sequence analysis revealed the existence of two PGK mRNA components in the patient's cells. The major component corresponds to the normal PGK mRNA except for A → C change at nucleotide position 755 counting from adenine of the chain initiation codon. The minor component contains 5′ region (52 bases) of intron 7 between exon 7 and exon 8. An inframe chain termination codon exists in the minor mRNA component, and the COOH-terminal half is expected to be deleted in the translation product. These results indicate that the low PGK activity in the patient's tissues is mainly due to retarded and aberrant pre-mRNA splicings caused by the change of the consensus 5′ splice sequence AGgt to a nonconsensus sequence CGgt at the junction between exon 7 and intron 7 of the variant gene.

References (0)

Cited by (27)

  • Recurrent episodes of myoglobinuria, mental retardation and seizures but no hemolysis in two brothers with phosphoglycerate kinase deficiency

    2016, Neuromuscular Disorders
    Citation Excerpt :

    The patient with PGK Fukuroi, in addition, displayed intellectual deficiency and abnormal EEG. In both cases qualitative changes to muscle fiber were minimal and no accumulation of glycogen was observed [6,7]. A phenotype similar to that of our patients (myopathy, mental retardation and no hemolysis) has also been described in the patient with PGK Hamamatsu (c.758T > C, p.(Ile253Thr)) [8,9].

  • Myopathic form of phosphoglycerate kinase (PGK) deficiency: A new case and pathogenic considerations

    2009, Neuromuscular Disorders
    Citation Excerpt :

    The most common association, seen in 11 of 33 reported patients (34%) is hemolytic anemia and CNS involvement (seizures, mental retardation, strokes) [7–17]. A careful review of the literature, including the present patient, shows that the purely myopathic presentation is a close second (9 of 33 patients, 27%) [8,18–26]. Isolated blood dyscrasia was reported in 6 patients (18%) [27–31], the association of myopathy and CNS dysfunction in 4 patients (12%) [32–35], the association of anemia and myopathy only in one patient (3%) [36], while all three tissues were involved in 2 patients (6%) [6].

  • Disorders of carbohydrate metabolism

    2007, Handbook of Clinical Neurology
    Citation Excerpt :

    Only one patient had myopathy and hemolytic anemia, while two patients showed involvement of all three tissues. The seven myopathic cases were clinically indistinguishable from McArdle disease, but muscle biopsies showed less severe glycogen accumulation (DiMauro et al., 1983; Tonin et al., 1992; Cohen‐Solal et al., 1994; Ookawara et al., 1996; Schroder et al., 1996; Aasly et al., 2000; Hamano et al., 2000). Mutations in PGK1 were identified in four of the seven myopathic patients.

  • The energy-less red blood cell is lost: Erythrocyte enzyme abnormalities of glycolysis

    2005, Blood
    Citation Excerpt :

    Fourteen different mutations in PGK1 have been described in association with PGK deficiency.40 Most of these mutations are missense mutants of which one, in addition to encoding a nonconserved Glu252Ala substitution, resulted in aberrant splicing with a consequent 90% reduction in mRNA levels.69 Pyruvate kinase catalyzes the irreversible phosphoryl group transfer from phosphoenolpyruvate to ADP, yielding pyruvate and the second molecule of ATP in glycolysis (Figure 1).

  • Glycogen storage myopathies

    2000, Neurologic Clinics
    Citation Excerpt :

    The gene spans 23 kbp and contains 10 introns.67 In at least 12 patients with PGK deficiency the molecular defects were defined; 5 had myopathy.22, 38, 84, 106, 118 All mutations were different and were missense, except for two splice junction mutations and a single-codon deletion.

View all citing articles on Scopus
View full text