De novo mutation of the β-globin gene initiation codon (ATG→AAG) in a Northern European

Waye, John S.; Patterson, Michael M.; Barr, Ronald D.; Chui, David H.K.

doi:10.1002/(sici)1096-8652(199711)56:3<179::aid-ajh8>3.0.co;2-v

Cited by 19 publications

(10 citation statements)

References 28 publications

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“…While this question is still unresolved, the data presented here suggest that N-terminally truncated b-globin fragments are less toxic than C-terminally truncated fragments. Furthermore, it must be noted that heterozygotes for the b-globin initiation codon mutation show a more severe hematological phenotype than those with mutations further 39, indicating that the synthesis of N-terminally truncated b-globin fragments may also have a subtle dominant negative effect (Waye et al 1997).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of escape from nonsense-mediated mRNA decay of human β-globin transcripts with nonsense mutations in the first exon

Neu‐Yilik

Amthor²,

Gehring³

et al. 2011

RNA

121

105

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The degradation of nonsense-mutated b-globin mRNA by nonsense-mediated mRNA decay (NMD) limits the synthesis of C-terminally truncated dominant negative b-globin chains and thus protects the majority of heterozygotes from symptomatic b-thalassemia. b-globin mRNAs with nonsense mutations in the first exon are known to bypass NMD, although current mechanistic models predict that such mutations should activate NMD. A systematic analysis of this enigma reveals that (1) b-globin exon 1 is bisected by a sharp border that separates NMD-activating from NMD-bypassing nonsense mutations and (2) the ability to bypass NMD depends on the ability to reinitiate translation at a downstream start codon. The data presented here thus reconcile the current mechanistic understanding of NMD with the observed failure of a class of nonsense mutations to activate this important mRNA quality-control pathway. Furthermore, our data uncover a reason why the position of a nonsense mutation alone does not suffice to predict the fate of the affected mRNA and its effect on protein expression.

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Section: Discussionmentioning

confidence: 99%

Mechanism of escape from nonsense-mediated mRNA decay of human β-globin transcripts with nonsense mutations in the first exon

Neu‐Yilik

Amthor²,

Gehring³

et al. 2011

RNA

121

105

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“…In their study, they showed that MRAP and MC2R interact and are co-localized in the endoplasmic reticulum and plasma membrane. Though not frequent, mutations in the initiation codon have been reported as a cause of human diseases (36)(37)(38). It has been demonstrated that initiation at non-AUG codons is inefficient in eukaryotic cells (39).…”

Section: Discussionmentioning

confidence: 99%

“…Mutations in the initiation codon may lead to a translation of mutant mRNA from a subsequent in-frame initiation codon, resulting in a truncated protein with a predictable severe loss of function. In patients with b-thalassemia, more severe anemia has been associated with different mutations in the initiation codon of the b-globin gene (37). More recently, Yu et al (40) showed that M1I mutation, due to a change of ATG to ATC, in the initiation codon of LPL gene results in a reduced catalytic activity of lipoprotein lipase.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity in the molecular basis of ACTH resistance syndrome.

Collares

Antunes‐Rodrigues²,

Moreira³

et al. 2008

European Journal of Endocrinology

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Objective: ACTH resistance syndromes are rare, autosomal, and genetically heterogeneous diseases that include familial glucocorticoid deficiency (FGD) and triple A syndrome. FGD has been shown to segregate with mutations in the gene coding for ACTH receptor (MC2R) or melanocortin 2 receptor accessory protein (MRAP), whereas mutations in the triple A syndrome (AAAS, Allgrove syndrome) gene have been found in segregation with triple A syndrome. We describe the clinical findings and molecular analysis of MC2R, MRAP, and AAAS genes in five Brazilian patients with ACTH resistance syndrome. Design and methods: Genomic DNA from patients and their unaffected relatives was extracted from peripheral blood leucocytes and amplified by PCR, followed by automated sequencing. Functional analysis was carried out using Y6 cells expressing wild-type and mutant MC2R. Results: All five patients showed low cortisol and elevated plasma ACTH levels. One patient had achalasia and alacrima, besides the symptoms of adrenal insufficiency. The molecular analysis of FGD patients revealed a novel p.Gly116Val mutation in the MC2R gene in one patient and p.Met1Ile mutation in the MRAP gene in another patient. Expression of p.Gly116Val MC2R mutant in Y6 cells revealed that this variant failed to stimulate cAMP production. The analysis of the AAAS gene in the patient with triple A syndrome showed a novel g.782_783delTG deletion. The molecular analysis of DNA from other two patients showed no mutation in MC2R, MRAP, or AAAS gene. Conclusions: In conclusion, the molecular basis of ACTH resistance syndrome is heterogeneous, segregating with genes coding for proteins involved with ACTH receptor signaling/expression or adrenal gland development and other unknown genes.European Journal of Endocrinology 159 61-68

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“…Different classes of HBB mutations underlie betathalassemia, in descending order of frequency: missense/nonsense [25,26], splicing [27], regulatory [28], small or gross gene deletions [27,29], including the common deletion of the terminal portion of HBB [30], gene insertions [31], small insertion-deletions [32], and complex rearrangements [33]. In rare instances, the causative defect is due to a deletion of the LCR [18], mutations in another gene within [34] or outside [16] the beta-globin locus.…”

Section: Variants Of Beta-thalassemiamentioning

confidence: 99%

Understanding Beta-Thalassemia with Focus on the Indian Subcontinent and the Middle East

Lahiry¹,

Al-Attar²,

Ra³

2008

TOHJ

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Beta-thalassemia is one of the most prevalent autosomal disorders in the world. Mutations in the HBB gene underlie deficiencies in hemoglobin production, which can interfere with oxygen delivery resulting in wide range of disease severity. Although >535 mutations have been characterized in the HBB gene, beta-thalassemia is broadly classified into three groups, based on clinical severity: beta-thalassemia major, beta-thalassemia intermedia and beta-thalassemia minor. In this article we review: 1) the molecular and biochemical basis of beta-thalassemia; 2) clinical features; 3) the range of common molecular variants of beta-thalassemia in a subset of geographic regions within the Indian Subcontinent and the Middle East; 4) potential molecular diagnostics; and 5) current and future treatments. We suggest that efforts to more completely characterize the HBB mutation distribution in high-risk areas, such as the Indian Subcontinent and the Middle East, may lead to improved diagnosis with earlier and more effective intervention strategies.

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De novo mutation of the β-globin gene initiation codon (ATG→AAG) in a Northern European

Cited by 19 publications

References 28 publications

Mechanism of escape from nonsense-mediated mRNA decay of human β-globin transcripts with nonsense mutations in the first exon

Mechanism of escape from nonsense-mediated mRNA decay of human β-globin transcripts with nonsense mutations in the first exon

Heterogeneity in the molecular basis of ACTH resistance syndrome.

Understanding Beta-Thalassemia with Focus on the Indian Subcontinent and the Middle East

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