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Article: Frame shift mutation, exon skipping, and a two-codon deletion caused by splice site mutations account for pyruvate kinase deficiency

TitleFrame shift mutation, exon skipping, and a two-codon deletion caused by splice site mutations account for pyruvate kinase deficiency
Authors
Issue Date1997
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
Blood, 1997, v. 89 n. 11, p. 4213-4218 How to Cite?
AbstractThree novel splice site mutations and two novel missense mutations were identified by molecular analysis of pyruvate kinase (PK) deficiency associated with hereditary nonspherocytic hemolytic anemia. A Nepalese PK variant, PK Kowloon, was found to have a homozygous transversion at the 5'- splice site of the seventh intervening sequence (IVS) of the L-type PK gene (Ivs7[+1]gt → tt). Using a reverse transcription polymerase chain reaction (RT-PCR) assay, we showed that the R-type PK mRNA in the proband's reticulocytes included the seventh IVS between the seventh and eighth exon, introducing a stop codon 3 nucleotides downstream of the mutated site. Consequently, the translational product may lack 44% of the R-PK polypeptide. A transition at the last nucleotide of axon 9 H (1269GCG → GCA) was found in a Japanese PK variant, PK 'Kamata.' The mutation did not alter the amino acid sequence, but caused skipping of the ninth exonic sequence in the R-PK transcripts. As a result, the affected R-type PK lost 51 amino acid residues (373Met-423Ala del). A transversion at the splice acceptor site of the third IVS (Ivs 3[-2]ag → tg) was identified in PK 'Aomori.' The mutation resulted in aberrant splicing at a cryptic splice site within exon 4, causing deletion of two codons in the aberrant R-PK transcript (95 Gly-96 Pro → del). Both PK 'Kamata' and PK 'Aomori' had a missense mutation on the other allele, 1044AAG → AAT (348Lys → Asn) and 1075CGC → TGC (359Arg → Cys), respectively. Although both 348Lys and 359Arg were located in the sixth loop of A domain (β/}a barrel, which has been shown to contain the substrate and cation binding sites, the degree of anemia was much more severe in PK 'Kamata' than PK 'Aomori,' possibly because the 51 amino acid deletion of PK 'Kamata' but the 2 amino-acid deletion of PK 'Aomori' may abolish PK catalytic activity.
Persistent Identifierhttp://hdl.handle.net/10722/148090
ISSN
2015 Impact Factor: 11.841
2015 SCImago Journal Rankings: 6.395
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorKanno, Hen_US
dc.contributor.authorFujii, Hen_US
dc.contributor.authorWei, DCen_US
dc.contributor.authorChan, LCen_US
dc.contributor.authorHirono, Aen_US
dc.contributor.authorTsukimoto, Ien_US
dc.contributor.authorMiwa, Sen_US
dc.date.accessioned2012-05-29T06:10:47Z-
dc.date.available2012-05-29T06:10:47Z-
dc.date.issued1997en_US
dc.identifier.citationBlood, 1997, v. 89 n. 11, p. 4213-4218en_US
dc.identifier.issn0006-4971en_US
dc.identifier.urihttp://hdl.handle.net/10722/148090-
dc.description.abstractThree novel splice site mutations and two novel missense mutations were identified by molecular analysis of pyruvate kinase (PK) deficiency associated with hereditary nonspherocytic hemolytic anemia. A Nepalese PK variant, PK Kowloon, was found to have a homozygous transversion at the 5'- splice site of the seventh intervening sequence (IVS) of the L-type PK gene (Ivs7[+1]gt → tt). Using a reverse transcription polymerase chain reaction (RT-PCR) assay, we showed that the R-type PK mRNA in the proband's reticulocytes included the seventh IVS between the seventh and eighth exon, introducing a stop codon 3 nucleotides downstream of the mutated site. Consequently, the translational product may lack 44% of the R-PK polypeptide. A transition at the last nucleotide of axon 9 H (1269GCG → GCA) was found in a Japanese PK variant, PK 'Kamata.' The mutation did not alter the amino acid sequence, but caused skipping of the ninth exonic sequence in the R-PK transcripts. As a result, the affected R-type PK lost 51 amino acid residues (373Met-423Ala del). A transversion at the splice acceptor site of the third IVS (Ivs 3[-2]ag → tg) was identified in PK 'Aomori.' The mutation resulted in aberrant splicing at a cryptic splice site within exon 4, causing deletion of two codons in the aberrant R-PK transcript (95 Gly-96 Pro → del). Both PK 'Kamata' and PK 'Aomori' had a missense mutation on the other allele, 1044AAG → AAT (348Lys → Asn) and 1075CGC → TGC (359Arg → Cys), respectively. Although both 348Lys and 359Arg were located in the sixth loop of A domain (β/}a barrel, which has been shown to contain the substrate and cation binding sites, the degree of anemia was much more severe in PK 'Kamata' than PK 'Aomori,' possibly because the 51 amino acid deletion of PK 'Kamata' but the 2 amino-acid deletion of PK 'Aomori' may abolish PK catalytic activity.en_US
dc.languageengen_US
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/en_US
dc.relation.ispartofBlooden_US
dc.subject.meshAnemia, Hemolytic, Congenital Nonspherocytic - Geneticsen_US
dc.subject.meshChilden_US
dc.subject.meshCodon - Geneticsen_US
dc.subject.meshFemaleen_US
dc.subject.meshFrameshift Mutationen_US
dc.subject.meshGene Deletionen_US
dc.subject.meshHumansen_US
dc.subject.meshInfanten_US
dc.subject.meshPyruvate Kinase - Deficiency - Geneticsen_US
dc.titleFrame shift mutation, exon skipping, and a two-codon deletion caused by splice site mutations account for pyruvate kinase deficiencyen_US
dc.typeArticleen_US
dc.identifier.emailChan, LC:chanlc@hkucc.hku.hken_US
dc.identifier.authorityChan, LC=rp00373en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.pmid9166866-
dc.identifier.scopuseid_2-s2.0-0030992689en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0030992689&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume89en_US
dc.identifier.issue11en_US
dc.identifier.spage4213en_US
dc.identifier.epage4218en_US
dc.identifier.isiWOS:A1997XD37900041-
dc.publisher.placeUnited Statesen_US

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