Molecular basis for nondeletion alpha-thalassemia in American blacks. Alpha 2(116GAG----UAG).

Liebhaber, S A; Coleman, Mary B.; Adams, Joel C.; Cash, F E; Steinberg, Martin H.

doi:10.1172/jci113041

Cited by 47 publications

(11 citation statements)

References 43 publications

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“…First, nonsense mutations frequently exert an effect on mRNA metabolism, resulting in a dramatic reduction in the steady-state level of cytoplasmic mRNA (Belgrader et al 1994). Secondly, a few nonsense mutations are associated with normal levels of cytoplasmic mRNA and are efficiently translated to generate truncated polypeptides (Lehrman et al 1987;Liebhaber et al 1987;Fojo et al 1989). The third documented outcome is that the exon containing the nonsense mutation is spliced out from the mature RNA, resulting in exon skipping.…”

Section: Discussionmentioning

confidence: 99%

Characterisation of two different nonsense mutations, C6792A and C6792G, causing skipping of exon 37 in the NF1 gene

et al. 1997

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Neurofibromatosis type 1 (NF1), characterised by peripheral neurofibromas, café-au-lait spots and iris Lisch nodules, is one of the most common inherited disorders. We have analysed exons 35 to 49 in 21 unrelated NF1 patients using reverse transcription-polymerase chain reaction and protein truncation analysis. In two unrelated patients we found skipping of exon 37 at the cDNA level. Sequence analysis of genomic DNA revealed the presence of a C6792A transversion in one patient and a C6792G transversion in a second patient; both transversions change the codon for tyrosine to a nonsense codon. Sequencing of the exonic sequences as well as the branch sites, and the 3' and 5' splice sites of exons 36, 37 and 38 did not reveal any additional sequence abnormality. This is the first report showing that nonsense mutations in the NF1 gene can induce the skipping of a constitutive exon.

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Section: Discussionmentioning

confidence: 99%

Characterisation of two different nonsense mutations, C6792A and C6792G, causing skipping of exon 37 in the NF1 gene

et al. 1997

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“…A nonsense mutation has also been described in the third exon of the a-globin gene, a-116 (UAG) (26). The a-116 mRNA accumulates in normal amounts.…”

Section: Discussionmentioning

confidence: 99%

Nonsense mutations in the human beta-globin gene affect mRNA metabolism.

Baserga

Benz

1988

Proc. Natl. Acad. Sci. U.S.A.

202

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A number of premature translation termination mutations (nonsense mutations) have been described in the human a-and (8-globin genes. Studies on mRNA isolated from patients with IP-thalassemia have shown that for both the (3-17 and the (8-39 mutations less than normal levels of (8-globin mRNA accumulate in peripheral blood cells. (The codon at which the mutation occurs designates the name of the mutation; there are 146 codons in human (3-globin mRNA.) In vitro studies using the cloned (1-39 gene have reproduced this effect in a heterologous transfection system and have suggested that the defect resides in intranuclear metabolism. We have asked if this phenomenon of decreased mRNA accumulation is a general property of nonsense mutations and if the effect depends on the location or the type of mutation. Toward this end, we have studied the effect of five nonsense mutations and two missense mutations on the expression of human (3-globin mRNA in a heterologous transfection system. In all cases studied, the presence of a translation termination codon correlates with a decrease in the steady-state level of mRNA. The data suggest that the metabolism of a mammalian mRNA is affected by the presence of a mutation that affects translation.Many of the steps in /-globin gene expression have been well-studied. Globin mRNA is transcribed from DNA, spliced, polyadenylylated, and then translated into protein in the cytoplasm. Less is known about the determinants of nuclear and cytoplasmic globin mRNA stability and about nuclear-cytoplasmic transport. The /3-39 gene causes thalassemia because it encodes a truncated nonfunctional globin protein chain. (The codon at which the mutation occurs designates the name of the mutation.) Although the nonsense mutation at codon 39 affects translation, studies from our laboratory and others suggest that this mutation has an additional unexpected effect on mRNA metabolism (1-8).

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“…These may involve altered intranuclear stability, abnormal nuclear to cytoplasmic transport of the mRNA, or decreased stability of the intracellular mRNA (27,28). However, two recent studies indicate that a nonsense mutation will not necessarily result in a decreased level of steady-state mRNA (29,30). Thus, normal mRNA levels have been identified for the LDL receptor and the ,B-globin chain in patients that have nonsense mutations of these genes.…”

Section: Discussionmentioning

confidence: 99%

A nonsense mutation in the apolipoprotein C-IIPadova gene in a patient with apolipoprotein C-II deficiency.

Fojo¹,

Parrott²,

Baggio³

et al. 1989

J. Clin. Invest.

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The apo C-II gene from a patient with apo C-1I deficiency has been sequenced after amplification by the polymerase chain reaction. A substitution of an adenosine for a guanosine at position 3002 in exon 3 of the patient's gene was identified by sequence analysis. This mutation leads to the introduction of a premature termination codon (TAA) at a position corresponding to amino acid 37 of mature apo C-II and to the formation of a new Rsa I restriction enzyme site not present in the normal apo C-II gene. Amplification of DNA from family members by the polymerase chain reaction and digestion with Rsa I established that the patient is a true homozygote for the mutation. Analysis of the patient's plasma by two-dimensional gel electrophoresis and immunoblotting detected an apo C-II that exhibited abnormal electrophoretic mobility. We propose that the C to A substitution in the apo C-Ipdova gene is the primary genetic defect that leads to premature termination and the synthesis of a truncated 36 amino acid apo C-II that is unable to activate lipoprotein lipase.

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Molecular basis for nondeletion alpha-thalassemia in American blacks. Alpha 2(116GAG----UAG).

Abstract: and the positioning of this nonsense mutation at the a2-globin gene locus are fully consistent with the observed a-thalassemia phenotype.

Cited by 47 publications

References 43 publications

Characterisation of two different nonsense mutations, C6792A and C6792G, causing skipping of exon 37 in the NF1 gene

Characterisation of two different nonsense mutations, C6792A and C6792G, causing skipping of exon 37 in the NF1 gene

Nonsense mutations in the human beta-globin gene affect mRNA metabolism.

A nonsense mutation in the apolipoprotein C-IIPadova gene in a patient with apolipoprotein C-II deficiency.

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