The 185delAG mutation (c.68_69delAG) in theBRCA1 gene triggers translation reinitiation at a downstream AUG codon

Buisson, Monique; Anczuków, Olga; Zetoune, Almoutassem Billah; Ware, Mark D.; Mazoyer, Sylvie

doi:10.1002/humu.20384

Cited by 57 publications

(56 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In b-globin, the proximity of the termination event to the AUG and to the 39 mRNP including the poly(A) binding protein C1 within the mRNA ''closed loop'' formation (Wells et al 1998) has been interpreted to mimic a proper position of termination, thus bypassing NMD (Eberle et al 2008;Ivanov et al 2008;Silva et al 2008;Singh et al 2008). In other cases, reinitiation of translation has been shown to play an important role (Zhang and Maquat 1997;Perrin-Vidoz et al 2002;Denecke et al 2004;Buisson et al 2006;Paulsen et al 2006).…”

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

119

102

View full text Add to dashboard Cite

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.

show abstract

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

119

102

View full text Add to dashboard Cite

show abstract

“…In contrast to the majority of premature termination codoninducing (PTC-inducing) BRCA1 mutations, previous studies demonstrated that BRCA1 185delAG and BRCA1 188del11 alleles were not subject to nonsense-mediated mRNA decay (NMD), leading to speculation that translation may continue after the PTC and prevent NMD (38,47). Using C-terminal-specific BRCA1 Abs, we confirmed that translation does occur after the BRCA1 185delAG -induced PTC, and we readily identified a protein product that was only slightly smaller in size compared with that of fulllength BRCA1 in SUM1315MO2 parental and resistant cells, probably starting at Met-297.…”

Section: Methodsmentioning

confidence: 99%

“…We next examined mRNA features that could impact the translation start site choice. Previous studies demonstrated that Met-48 had a weak, but Met-128 and Met-297 had similar-strength, Kozak consensus motifs (38). Hairpin structures at the 5′ end of mRNA translation start sites commonly block translation initiation by preventing the 40S ribosomal subunit from binding (39)(40)(41).…”

Section: Sum1315mo2mentioning

confidence: 99%

RING domain–deficient BRCA1 promotes PARP inhibitor and platinum resistance

Wang¹,

Krais²,

Bernhardy³

et al. 2016

Journal of Clinical Investigation

View full text Add to dashboard Cite

“…37 Cases of premature protein termination variation early in the gene followed by reinitiation of translation at a downstream start codon in other genes are not rare, suggesting an alternative to escape NMD. 38,39 In many cases of reinitiation, N-terminally truncated proteins are predicted to rescue the patient from a more severe loss-of-function phenotype, including truncating variants within the first exon of DMD gene, resulting in the milder Becker muscular dystrophy instead of the predicted more severe Duchenne muscular dystrophy (DMD). 40 In ARX, both the N-terminal octapeptide domain and the region flanking polyalanine tract 4 function as repressor domains.…”

Section: Discussionmentioning

confidence: 99%

Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX

et al. 2015

View full text Add to dashboard Cite

Mutations in the Aristaless-related homeobox gene (ARX) lead to a range of X-linked intellectual disability phenotypes, with truncating variants generally resulting in severe X-linked lissencephaly with ambiguous genitalia (XLAG), and polyalanine expansions and missense variants resulting in infantile spasms. We report two male patients with early-onset infantile spasms in whom a novel c.34G4T (p.(E12*)) variant was identified in the ARX gene. A similar variant c.81C4G (p.(Y27*)), has previously been described in two affected cousins with early-onset infantile spasms, leading to reinitiation of ARX mRNA translation resulting in an N-terminal truncated protein. We show that the novel c.34G4T (p.(E12*)) variant also reinitiated mRNA translation at the next AUG codon (c.121-123 (p.M41)), producing the same N-terminally truncated protein. The production of both of these truncated proteins was demonstrated to be at markedly reduced levels using in vitro cell assays. Using luciferase reporter assays, we demonstrate that transcriptional repression capacity of ARX was diminished by both the loss of the N-terminal corepressor octapeptide domain, as a consequence of truncation, and the marked reduction in mutant protein expression. Our study indicates that premature termination mutations very early in ARX lead to reinitiation of translation to produce N-terminally truncated protein at markedly reduced levels of expression. We conclude that even low levels of N-terminally truncated ARX is sufficient to improve the patient's phenotype compared with the severe phenotype of XLAG that includes malformations of the brain and genitalia normally seen in complete loss-of-function mutations in ARX.

show abstract

The 185delAG mutation (c.68_69delAG) in theBRCA1 gene triggers translation reinitiation at a downstream AUG codon

Cited by 57 publications

References 22 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

RING domain–deficient BRCA1 promotes PARP inhibitor and platinum resistance

Reinitiation of mRNA translation in a patient with X-linked infantile spasms with a protein-truncating variant in ARX

Contact Info

Product

Resources

About