Disruption of<i>TWIST1</i>translation by 5′ UTR variants in Saethre-Chotzen syndrome

Zhou, Yan; Koelling, Nils; Fenwick, Aimée L.; McGowan, Simon J.; Calpena, Eduardo; Wall, Steven A.; Smithson, Sarah; Twigg, Stephen R.F.

doi:10.1002/humu.23598

Cited by 10 publications

(18 citation statements)

References 38 publications

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“…In this individual, we identified compound‐heterozygous variants c.1311G>A; p.W437* and c.‐38 T>A (Table ); the latter introduces an alternative ATG codon out‐of‐frame with the canonical start site. Such features in mRNA, also known as upstream open reading frames (uORFs), can cause widespread protein expression changes in humans, in some cases resulting in disease . We therefore speculated that c.‐38T>A might alter the amount of wild‐type LZTR1 protein.…”

Section: Resultsmentioning

confidence: 99%

“…This analysis suggested that, while both sites have an equally strong identity with the [A/G]XXATGG Kozak consensus sequence, the novel ATG could have a higher reliability in initiating translation (Supplementary note 2). A reporter assay using a dual luciferase strategy was performed, as described . The ratio of renilla to firefly luciferase was consistently reduced to 77% to 85% for the mutant 5’‐UTR in comparison to the WT (Supplementary note 2).…”

Section: Resultsmentioning

confidence: 99%

“…Several examples exist in the literature of disease‐causing variants in 5‐‘UTRs and reporter gene assays such as the one used here are commonly used to confirm the effect of such variants upon translation. Examples include a de novo c.‐107G>A variant in SLC2A1 found in a patient with glucose transporter deficiency syndrome and c.‐263C>A/c.‐255G>A variants in TWIST1 in patients with Saethre‐Chotzen syndrome …”

Section: Discussionmentioning

confidence: 99%

“…A reporter assay using a dual luciferase strategy was performed, as described. 23,25 The ratio of renilla to firefly luciferase was consistently reduced to 77% to 85% for the mutant 5'-UTR in comparison to the WT (Supplementary note 2). AR inheritance had been suspected in this family as a male sibling (despite normal early scans) developed polyhydramnios at 20 weeks gestation.…”

Section: Phenotype Comparisons Using Unbiased Hpo Termsmentioning

confidence: 99%

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Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

et al. 2019

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Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1‐ associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly‐acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound‐heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss‐of‐function mutations in NEB , consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities ( P = 0.0005), supporting a causal role for LZTR1 . Second, targeted sequencing of eight unsolved NS‐like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.‐38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1‐4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Phenotype Comparisons Using Unbiased Hpo Termsmentioning

confidence: 99%

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Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

et al. 2019

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“…The 5ʹUTR variants that alter uORFs have been described in association with the etiology of Mendelian disorders. Such variants may create an uAUG resulting in new uORF (Romanelli Tavares et al, 2019; von Bohlen et al, 2017; Wright et al, 2021; Zhou et al, 2018), or may disrupt the existing uORFs (Occhi et al, 2013; Wen et al, 2009). Analysis of allele frequency spectrum of variants in 15,708 individual whole‐genome sequencing data from the Genome Aggregation Database (gnomAD) reveals that uAUG‐creating variants and variants that disrupt uORF stop codons are under strong negative selection (Whiffin et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Upstream ORF frameshift variants in thePAX65ʹUTR cause congenital aniridia

et al. 2021

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Congenital aniridia (AN) is a severe autosomal dominant panocular disorder associated with pathogenic variants in the PAX6 gene. Previously, we performed a molecular genetic study of a large cohort of Russian patients with AN and revealed four noncoding nucleotide variants in the PAX6 5ʹUTR. 14 additional PAX6-5ʹUTR variants were also reported in the literature, but the mechanism of their pathogenicity remained unclear. In the present study, we experimentally analyze five patient-derived PAX6 5ʹUTR-variants: four variants that we identified in Russian patients (c.-128-2delA, c.-125dupG, c.-122dupG, c.-118_-117del) and one previously reported (c.-52+5G>C). We show that the variants lead to a decrease in the protein translation efficiency, while mRNA expression level is not significantly reduced. Two of these variants also affect splicing. Furthermore, we predict and experimentally validate the presence of an evolutionarily conserved small uORF in the PAX6 5ʹUTR.All studied variants lead to the frameshift of the uORF, resulting in its extension.This extended out-of-frame uORF overlaps with the downstream CDS and thereby reduces its translation efficiency. We conclude that the uORF frameshift may be the main mechanism of pathogenicity for at least 15 out of 18 known PAX6 5ʹUTR variants. Moreover, we predict additional uORFs in the PAX6 5ʹUTR.

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Translational Regulation by Upstream Open Reading Frames and Its Relevance to Human Genetic Disease

Fernandes

Romão

2020

Encyclopedia of Life Sciences

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Upstream open reading frames (uORFs) are cis ‐acting elements, located before or overlapped with the main coding ORF (mORF), that regulate cap‐dependent translation efficiency in a transcript‐specific manner. More than half of the human transcripts bear at least one uORF. In addition, it has been recently revealed that many of these uORFs initiate at non‐AUG codons, which significantly increases the complexity and diversity of the human translatome. These regulons are considered repressors of downstream translation but, in some biological contexts, they induce mORF expression. There are several the mechanisms by which AUG and non‐AUG uORFs regulate gene expression, allowing the cell to control transcript‐specific translation according to its needs. Also, we describe several examples of uORF genetic variants associated with human genetic diseases. Studying these cases and understanding the resultant abnormal mechanisms of uORF‐mediated translational control is of extreme importance for the development of new therapeutic strategies. Key Concepts Upstream open reading frames (uORFs) are cis ‐acting translational regulatory elements present within the 5′ leader sequence of mRNAs. uORFs can regulate gene expression by repressing or promoting translation of the downstream main ORF (mORF), according to the cellular environment. The number of uORFs, the intercistronic distance, the overlap with the mORF and the context of the initiation codon are the uORF‐related structural features that most influence their translational regulatory capacity. uORF‐mediated repression of mORF translation is usually achieved by ribosome dissociation, ribosome stalling, induction of nonsense‐mediated mRNA decay (NMD) or production of inhibitory peptides. uORF‐mediated induction of mORF translation is usually achieved by ribosome bypass or translation reinitiation. uORFs initiated by non‐AUG codons are more frequent than previously appreciated, having important biological functions. uORF‐altering polymorphisms and mutations, which create, disrupt or change a uORF, can cause human genetic diseases. Studying and understanding the uORF‐mediated mechanisms of gene expression regulation may provide knowledge to develop novel therapies for several human diseases.

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Disruption ofTWIST1translation by 5′ UTR variants in Saethre-Chotzen syndrome

Cited by 10 publications

References 38 publications

Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

Upstream ORF frameshift variants in thePAX65ʹUTR cause congenital aniridia

Translational Regulation by Upstream Open Reading Frames and Its Relevance to Human Genetic Disease

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