Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans

Alzahrani, Fatema; Kuwahara, Hiroyuki; Long, Yongkang; Al‐Owain, Mohammed; Tohary, Mohamed; AlSayed, Moeenaldeen; Mahnashi, Mohammed; Fathi, Lana; Alnemer, Maha; Al‐Hamed, Mohamed H.; Lemire, Gabrielle; Boycott, Kym M.; Hashem, Mais; Han, Wenkai; Al‐Maawali, Almundher; Mahrizi, Feisal Al; Al‐Thihli, Khalid; Gao, Xin; Alkuraya, Fowzan S.

doi:10.1016/j.ajhg.2020.11.007

Cited by 21 publications

(31 citation statements)

References 25 publications

(32 reference statements)

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“…The proband has a very similar phenotype to those described previously (Alzahrani et al, 2020), but in addition manifested unilateral microphthalmia; this latter ocular finding was previously described among two out of six patients with biallelic SMG9 variants (Shaheen et al, 2016). Given the known combined role of SMG8 and SMG9 gene products, that is, SMG8 and SMG9, respectively, in the control of gene expression it is not surprising to find associated microphthalmia in our patient.…”

Section: Introductionsupporting

confidence: 87%

Expanding the phenotypic and allelic spectrum of SMG8: Clinical observations reveal overlap with SMG9‐associated disease trait

Abdel-Salam

Duan

Abdel‐Hamid

et al. 2021

American J of Med Genetics Pt A

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SMG8 (MIM *617315) is a regulatory subunit involved in nonsense-mediated mRNA decay (NMD), a cellular protective pathway that regulates mRNA transcription, transcript stability, and degrades transcripts containing premature stop codons. SMG8 binds SMG9 and SMG1 to form the SMG1C complex and inhibit the kinase activity of SMG1. Biallelic deleterious variants in SMG9 are known to cause a heart and brain malformation syndrome (HBMS; MIM #616920), whereas biallelic deleterious variants in SMG8 were recently described to cause a novel neurodevelopmental disorder (NDD) with dysmorphic facies and cataracts, now defined as Alzahrani-Kuwahara syndrome (ALKUS: MIM #619268). Only eight subjects from four families with ALKUS have been described to date. Through research reanalysis of a nondiagnostic clinical exome, we identified a subject from a fifth unrelated family with a homozygous deleterious variant in SMG8 and features consistent with ALKUS. Interestingly, the subject also had unilateral microphthalmia, a clinical feature that has been described in SMG9-related disorder. Our study expands the phenotypic spectrum of SMG8-related disorder, demonstrates an overlapping phenotype between SMG8-and SMG9-related rare disease traits, provides further evidence for the SMG8 and SMG9 protein interactions, and highlights the importance of revisiting nondiagnostic exome data to identify and affirm emerging novel genes for rare disease traits.

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Section: Introductionsupporting

confidence: 87%

Expanding the phenotypic and allelic spectrum of SMG8: Clinical observations reveal overlap with SMG9‐associated disease trait

Abdel-Salam

Duan

Abdel‐Hamid

et al. 2021

American J of Med Genetics Pt A

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“…Interestingly, we found that HOTAIR might bind to UPF1. UPF1 is involved in a highly conserved RNA degradation pathway called nonsense-mediated RNA decay (NMD), which can lead to the degradation of mRNAs ( Alzahrani et al., 2020 ; Deka et al., 2020 ). Based on the above information, we hypothesized that HOTAIR might mediate the progression of ICH by binding to UPF1.…”

Section: Introductionmentioning

confidence: 99%

Paeonol inhibits the progression of intracerebral haemorrhage by mediating the HOTAIR/UPF1/ACSL4 axis

et al. 2021

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Intracerebral haemorrhage (ICH) is a devastating subtype of stroke with high morbidity and mortality. It has been reported that paeonol (PAN) inhibits the progression of ICH. However, the mechanism by which paeonol mediates the progression of ICH remains unclear. To mimic ICH in vitro, neuronal cells were treated with hemin. An in vivo model of ICH was established to detect the effect of paeonol on ferroptosis in neurons during ICH. Cell viability was tested by MTT assay. Furthermore, cell injury was detected by GSH, MDA and ROS assays. Ferroptosis was examined by iron assay. RT-qPCR and western blotting were used to detect gene and protein expression, respectively. The correlation among HOTAIR, UPF1 and ACSL4 was explored by FISH, RNA pull-down and RIP assays. Paeonol significantly inhibited the ferroptosis of neurons in ICH mice. In addition, paeonol significantly reversed hemin-induced injury and ferroptosis in neurons, while this phenomenon was notably reversed by HOTAIR overexpression. Moreover, paeonol notably inhibited ferroptosis in hemin-treated neuronal cells via inhibition of ACSL4. Additionally, HOTAIR bound to UPF1, and UPF1 promoted the degradation of ACSL4 by binding to ACSL4. Furthermore, HOTAIR overexpression reversed paeonol-induced inhibition of ferroptosis by mediating the UPF1/ACSL4 axis. Paeonol inhibits the progression of ICH by mediating the HOTAIR/UPF1/ACSL4 axis. Therefore, paeonol might serve as a new agent for the treatment of ICH.

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“…In the case of SMG1, the two interacting factors SMG8 and SMG9 have been linked to dysregulated NMD and neurodevelopmental disorders in humans ( Alzahrani et al, 2020 ; Shaheen et al, 2016 ; Yamashita et al, 2009 ). Previous cryo-electron microscopy (cryo-EM) studies have revealed the molecular interactions that underpin the structure of the human SMG1-SMG8-SMG9 complex ( Gat et al, 2019 ; Zhu et al, 2019 ) and the determinants with which it recognizes and phosphorylates UPF1 peptides with specific Leu-Ser-Gln (LSQ) motifs ( Langer et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8

Langer

Bonneau

Gat

et al. 2021

eLife

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The PI3K-related kinase (PIKK) SMG1 monitors progression of metazoan nonsense-mediated mRNA decay (NMD) by phosphorylating the RNA helicase UPF1. Previous work has shown that the activity of SMG1 is impaired by small molecule inhibitors, is reduced by the SMG1 interactors SMG8 and SMG9, and is downregulated by the so-called SMG1 insertion domain. However, the molecular basis for this complex regulatory network has remained elusive. Here, we present cryo-electron microscopy reconstructions of human SMG1-9 and SMG1-8-9 complexes bound to either a SMG1 inhibitor or a non-hydrolyzable ATP analogue at overall resolutions ranging from 2.8 to 3.6 Å. These structures reveal the basis with which a small molecule inhibitor preferentially targets SMG1 over other PIKKs. By comparison with our previously reported substrate-bound structure (Langer et al. 2020), we show that the SMG1 insertion domain can exert an autoinhibitory function by directly blocking the substrate binding path as well as overall access to the SMG1 kinase active site. Together with biochemical analysis, our data indicate that SMG1 autoinhibition is stabilized by the presence of SMG8. Our results explain the specific inhibition of SMG1 by an ATP-competitive small molecule, provide insights into regulation of its kinase activity within the NMD pathway, and expand the understanding of PIKK regulatory mechanisms in general.

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Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans

Cited by 21 publications

References 25 publications

Expanding the phenotypic and allelic spectrum of SMG8: Clinical observations reveal overlap with SMG9‐associated disease trait

Expanding the phenotypic and allelic spectrum of SMG8: Clinical observations reveal overlap with SMG9‐associated disease trait

Paeonol inhibits the progression of intracerebral haemorrhage by mediating the HOTAIR/UPF1/ACSL4 axis

Cryo-EM reconstructions of inhibitor-bound SMG1 kinase reveal an autoinhibitory state dependent on SMG8

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