<i>DMD</i>exon 1 truncating point mutations: Amelioration of phenotype by alternative translation initiation in exon 6

Gurvich, Olga L.; Maiti, Baijayanta; Weiss, Robert B.; Aggarwal, Gaurav; Howard, Michael; Flanigan, Kevin M.

doi:10.1002/humu.20913

Cited by 68 publications

(61 citation statements)

References 23 publications

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“…These include the genes for RAG1 (Santagata et al 2000), NBS1 (Maser et al 2001 (Puel et al 2006), IkBa (McDonald et al 2007), PHOX2B (Trochet et al 2009), DMD (Gurvich et al 2009), and FAC (Yamashita et al 1996). A notable exception is the expression of a DN25 isoform of TP63 expressed from an allele with a nonsense mutation at codon 11 that manifests dominant effects and is associated with a Rapp-Hodkin/ Hay-Wells like syndrome (Rinne et al 2008).…”

Section: Discussionmentioning

confidence: 44%

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: 44%

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

View full text Add to dashboard Cite

show abstract

“…Based on the molecular weight of the truncated protein and the sequence of the KCNQ1 gene, we hypothesized that because of the mutation in the original translation initiation site, the protein synthesis might start from the second initiation site at position 583 in exon 2 of KCNQ1 gene, generating a truncated protein missing the initial 158 residues compared to the full length of KCNQ1 protein. The mechanism was first described in the inherited arrhythmia syndromes, although it has been observed in other diseases (18)(19)(20). Ozisik et al found that an alternate translation initiation site circumvented an aminoterminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenital (18).…”

Section: Discussionsupporting

confidence: 42%

Novel compound heterozygous mutations T2C and 1149insT in the KCNQ1 gene cause Jervell and Lange-Nielsen syndrome

2011

Int J Mol Med

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Abstract. Mutations in the KCNQ1 gene account for more than 90% of the individuals with Jervell and Lange-Nielsen syndrome (JLNS). In this study, we identified and characterized two novel KCNQ1 mutations that caused JLNS. A 6-year-old deaf girl suffering from recurrent syncope had a documented electrocardiogram with polymorphic ventricular fibrillation since the age of 4 years. The baseline electrocardiogram showed a significantly prolonged corrected QT interval (524 msec). Genetic analysis revealed that the proband carried two heterozygous mutations of T2c and 1149insT in the KCNQ1 gene on separate alleles. Patch-clamp analysis demonstrated that the T2C mutation resulted in significant reduction in the slowly activated delayed rectifier current (I Ks ). Furthermore, western blot analysis and confocal imaging revealed that the T2c mutation produced a truncated protein with trafficking defects. In contrast, the 1149insT mutation failed to generate any measurable current, consistent with no protein expression in both the cell membrane and cytoplasm. Moreover, co-expression of the T2c and 1149insT mutations significantly reduced the peak tail current density to 8.27% of the wild-type (wT) current value, while co-transfected wT channels with either T2c or 1149insT mutant channels produced comparable current and channel kinetics to that of wT channels. Our study demonstrates that the compound heterozygous mutations T2c and 1149insT cause the 'loss-offunction' of the I Ks that may account for the clinical phenotype of the proband. Multiple mechanisms have been involved in the pathogenesis of 'loss-of-function' of I Ks .

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“…Similar observations have been made for mutations of DMD . Encoded in exon 1, the c.9G>A (p.Tyr3*) variant is expected to cause a severe Duchenne muscular dystrophy (DMD); however, the clinical presentation is that of the milder Becker muscular dystrophy [Gurvich et al, 2009]. Immunoblot analysis of dystrophin detected a protein of reduced size consistent with translational reinitiation within exon 6.…”

Section: Discussionmentioning

confidence: 99%

Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome

Cain

Kim

Quast

et al. 2017

American J of Med Genetics Pt A

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Pathogenic variants in PHOX2B lead to congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by autonomic dysregulation and hypoventilation typically presenting in the neonatal period, although a milder late-onset (LO) presentation has been reported. More than 90% of cases are caused by polyalanine repeat mutations (PARMs) in the C-terminus of the protein; however non-polyalanine repeat mutations (NPARMs) have been reported. Most NPARMs are located in exon 3 of PHOX2B and result in a more severe clinical presentation including Hirschsprung disease (HSCR) and/or peripheral neuroblastic tumors (PNTs). A previously reported nonsense pathogenic variant in exon 1 of a patient with LO-CCHS and no HSCR or PNTs leads to translational reinitiation at a downstream AUG codon producing an N-terminally truncated protein. Here we report additional individuals with nonsense pathogenic variants in exon 1 of PHOX2B. In vitro analyses were used to determine if these and other reported nonsense variants in PHOX2B exon 1 produced N-terminally truncated proteins. We found that all tested nonsense variants in PHOX2B exon 1 produced a truncated protein of the same size. This truncated protein localized to the nucleus and transactivated a target promoter. These data suggest that nonsense pathogenic variants in the first exon of PHOX2B likely escape nonsense mediated decay (NMD) and produce N-terminally truncated proteins functionally distinct from those produced by the more common PARMs.

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DMDexon 1 truncating point mutations: Amelioration of phenotype by alternative translation initiation in exon 6

Cited by 68 publications

References 23 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

Novel compound heterozygous mutations T2C and 1149insT in the KCNQ1 gene cause Jervell and Lange-Nielsen syndrome

Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome

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