Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene

Michele Young, Hiroshi Inaba, Leon W. Hoyer, Miyoko Higuchi, Haig Kazazian, Stylianos E. Antonarakis

Research output: Contribution to journalArticle

Abstract

Although the molecular defect in patients in a Japanese family with mild to moderately severe hemophilia A was a deletion of a single nucleotide T within an A 8TA 2 sequence of exon 14 of the factor VIII gene, the severity of the clinical phenotype did not correspond to that expected of a frameshift mutation. A small amount of functional factor VIII protein was detected in the patient's plasma. Analysis of DNA and RNA molecules from normal and affected individuals and in vitro transcription/translation suggested a partial correction of the molecular defect, because of the following: (i) DNA replication/RNA transcription errors resulting in restoration of the reading frame and/or (ii) 'ribosomal frameshifting' resulting in the production of normal factor VIII polypeptide and, thus, in a milder than expected hemophilia A. All of these mechanisms probably were promoted by the longer run of adenines, A 10 instead of A 8TA 2, after the delT. Errors in the complex steps of gene expression therefore may partially correct a severe frameshift defect and ameliorate an expected severe phenotype.

Original languageEnglish (US)
Pages (from-to)565-573
Number of pages9
JournalAmerican Journal of Human Genetics
Volume60
Issue number3
StatePublished - Mar 1997

Fingerprint

Factor VIII
Hemophilia A
Ribosomal Frameshifting
RNA
Genes
Phenotype
Reading Frames
Frameshift Mutation
antineoplaston A10
Adenine
DNA Replication
Exons
Nucleotides
Gene Expression
Peptides
DNA
Proteins

ASJC Scopus subject areas

  • Genetics

Cite this

Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene. / Young, Michele; Inaba, Hiroshi; Hoyer, Leon W.; Higuchi, Miyoko; Kazazian, Haig; Antonarakis, Stylianos E.

In: American Journal of Human Genetics, Vol. 60, No. 3, 03.1997, p. 565-573.

Research output: Contribution to journalArticle

Young, Michele ; Inaba, Hiroshi ; Hoyer, Leon W. ; Higuchi, Miyoko ; Kazazian, Haig ; Antonarakis, Stylianos E. / Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene. In: American Journal of Human Genetics. 1997 ; Vol. 60, No. 3. pp. 565-573.
@article{ecb378c9b2544f349986f3aa386f28aa,
title = "Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene",
abstract = "Although the molecular defect in patients in a Japanese family with mild to moderately severe hemophilia A was a deletion of a single nucleotide T within an A 8TA 2 sequence of exon 14 of the factor VIII gene, the severity of the clinical phenotype did not correspond to that expected of a frameshift mutation. A small amount of functional factor VIII protein was detected in the patient's plasma. Analysis of DNA and RNA molecules from normal and affected individuals and in vitro transcription/translation suggested a partial correction of the molecular defect, because of the following: (i) DNA replication/RNA transcription errors resulting in restoration of the reading frame and/or (ii) 'ribosomal frameshifting' resulting in the production of normal factor VIII polypeptide and, thus, in a milder than expected hemophilia A. All of these mechanisms probably were promoted by the longer run of adenines, A 10 instead of A 8TA 2, after the delT. Errors in the complex steps of gene expression therefore may partially correct a severe frameshift defect and ameliorate an expected severe phenotype.",
author = "Michele Young and Hiroshi Inaba and Hoyer, {Leon W.} and Miyoko Higuchi and Haig Kazazian and Antonarakis, {Stylianos E.}",
year = "1997",
month = "3",
language = "English (US)",
volume = "60",
pages = "565--573",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Partial correction of a severe molecular defect in hemophilia A, because of errors during expression of the factor VIII gene

AU - Young, Michele

AU - Inaba, Hiroshi

AU - Hoyer, Leon W.

AU - Higuchi, Miyoko

AU - Kazazian, Haig

AU - Antonarakis, Stylianos E.

PY - 1997/3

Y1 - 1997/3

N2 - Although the molecular defect in patients in a Japanese family with mild to moderately severe hemophilia A was a deletion of a single nucleotide T within an A 8TA 2 sequence of exon 14 of the factor VIII gene, the severity of the clinical phenotype did not correspond to that expected of a frameshift mutation. A small amount of functional factor VIII protein was detected in the patient's plasma. Analysis of DNA and RNA molecules from normal and affected individuals and in vitro transcription/translation suggested a partial correction of the molecular defect, because of the following: (i) DNA replication/RNA transcription errors resulting in restoration of the reading frame and/or (ii) 'ribosomal frameshifting' resulting in the production of normal factor VIII polypeptide and, thus, in a milder than expected hemophilia A. All of these mechanisms probably were promoted by the longer run of adenines, A 10 instead of A 8TA 2, after the delT. Errors in the complex steps of gene expression therefore may partially correct a severe frameshift defect and ameliorate an expected severe phenotype.

AB - Although the molecular defect in patients in a Japanese family with mild to moderately severe hemophilia A was a deletion of a single nucleotide T within an A 8TA 2 sequence of exon 14 of the factor VIII gene, the severity of the clinical phenotype did not correspond to that expected of a frameshift mutation. A small amount of functional factor VIII protein was detected in the patient's plasma. Analysis of DNA and RNA molecules from normal and affected individuals and in vitro transcription/translation suggested a partial correction of the molecular defect, because of the following: (i) DNA replication/RNA transcription errors resulting in restoration of the reading frame and/or (ii) 'ribosomal frameshifting' resulting in the production of normal factor VIII polypeptide and, thus, in a milder than expected hemophilia A. All of these mechanisms probably were promoted by the longer run of adenines, A 10 instead of A 8TA 2, after the delT. Errors in the complex steps of gene expression therefore may partially correct a severe frameshift defect and ameliorate an expected severe phenotype.

UR - http://www.scopus.com/inward/record.url?scp=0031017506&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031017506&partnerID=8YFLogxK

M3 - Article

VL - 60

SP - 565

EP - 573

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 3

ER -