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

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

doi:10.1016/j.ajhg.2020.11.007

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

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

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Abstract

We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.

Original language	English (US)
Journal	American Journal of Human Genetics
DOIs	https://doi.org/10.1016/j.ajhg.2020.11.007
State	Published - Nov 25 2020

Bibliographical note

KAUST Repository Item: Exported on 2020-11-30
Acknowledged KAUST grant number(s): BAS/1/1624-01, FCC/1/1976-18-01, FCC/1/1976-23-01, FCC/1/1976-25-01, FCC/1/1976-26-01, REI/1/0018-01-01, REI/1/4216-01-01, URF/1/4098-01-01.
Acknowledgements: We thank the study participants for their enthusiastic participation. We also thank the Sequencing and Genotyping Core Facilities at KFSRHC for their technical help. This work was supported by King Abdullah University of Science and Technology, Office of Sponsored Research under Awards BAS/1/1624-01, FCC/1/1976-18-01, FCC/1/1976-23-01, FCC/1/1976-25-01, FCC/1/1976-26-01, REI/1/0018-01-01, REI/1/4216-01-01, and URF/1/4098-01-01. This work was also supported by His Majesty Trust Funds at the Sultan Qaboos University, study code SR/MED/GENT/16/01.

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AlZahrani, F., Kuwahara, H., Long, Y., Al-Owain, M., Tohary, M., AlSayed, M., Mahnashi, M., Fathi, L., Alnemer, M., Al-Hamed, M. H., Lemire, G., Boycott, K. M., Hashem, M., Han, W., Al-Maawali, A., Al Mahrizi, F., Al-Thihli, K., Gao, X., & Alkuraya, F. S. (2020). Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans. American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2020.11.007

@article{905bef096cc44057a091715f44775c31,

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

abstract = "We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.",

author = "Fatema AlZahrani and Hiroyuki Kuwahara and Yongkang Long and Mohammed Al-Owain and Mohamed Tohary and Moeenaldeen AlSayed and Mohammed Mahnashi and Lana Fathi and Maha Alnemer and Al-Hamed, {Mohamed H} and Gabrielle Lemire and Boycott, {Kym M} and Mais Hashem and Wenkai Han and Almundher Al-Maawali and {Al Mahrizi}, Feisal and Khalid Al-Thihli and Xin Gao and Alkuraya, {Fowzan S}",

note = "KAUST Repository Item: Exported on 2020-11-30 Acknowledged KAUST grant number(s): BAS/1/1624-01, FCC/1/1976-18-01, FCC/1/1976-23-01, FCC/1/1976-25-01, FCC/1/1976-26-01, REI/1/0018-01-01, REI/1/4216-01-01, URF/1/4098-01-01. Acknowledgements: We thank the study participants for their enthusiastic participation. We also thank the Sequencing and Genotyping Core Facilities at KFSRHC for their technical help. This work was supported by King Abdullah University of Science and Technology, Office of Sponsored Research under Awards BAS/1/1624-01, FCC/1/1976-18-01, FCC/1/1976-23-01, FCC/1/1976-25-01, FCC/1/1976-26-01, REI/1/0018-01-01, REI/1/4216-01-01, and URF/1/4098-01-01. This work was also supported by His Majesty Trust Funds at the Sultan Qaboos University, study code SR/MED/GENT/16/01.",

year = "2020",

month = nov,

day = "25",

doi = "10.1016/j.ajhg.2020.11.007",

language = "English (US)",

journal = "American Journal of Human Genetics",

issn = "0002-9297",

publisher = "Cell Press",

}

AlZahrani, F, Kuwahara, H, Long, Y, Al-Owain, M, Tohary, M, AlSayed, M, Mahnashi, M, Fathi, L, Alnemer, M, Al-Hamed, MH, Lemire, G, Boycott, KM, Hashem, M, Han, W, Al-Maawali, A, Al Mahrizi, F, Al-Thihli, K, Gao, X & Alkuraya, FS 2020, 'Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans.', American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2020.11.007

TY - JOUR

T1 - Recessive, Deleterious Variants in SMG8 Expand the Role of Nonsense-Mediated Decay in Developmental Disorders in Humans.

AU - AlZahrani, Fatema

AU - Kuwahara, Hiroyuki

AU - Long, Yongkang

AU - Al-Owain, Mohammed

AU - Tohary, Mohamed

AU - AlSayed, Moeenaldeen

AU - Mahnashi, Mohammed

AU - Fathi, Lana

AU - Alnemer, Maha

AU - Al-Hamed, Mohamed H

AU - Lemire, Gabrielle

AU - Boycott, Kym M

AU - Hashem, Mais

AU - Han, Wenkai

AU - Al-Maawali, Almundher

AU - Al Mahrizi, Feisal

AU - Al-Thihli, Khalid

AU - Gao, Xin

AU - Alkuraya, Fowzan S

N1 - KAUST Repository Item: Exported on 2020-11-30 Acknowledged KAUST grant number(s): BAS/1/1624-01, FCC/1/1976-18-01, FCC/1/1976-23-01, FCC/1/1976-25-01, FCC/1/1976-26-01, REI/1/0018-01-01, REI/1/4216-01-01, URF/1/4098-01-01. Acknowledgements: We thank the study participants for their enthusiastic participation. We also thank the Sequencing and Genotyping Core Facilities at KFSRHC for their technical help. This work was supported by King Abdullah University of Science and Technology, Office of Sponsored Research under Awards BAS/1/1624-01, FCC/1/1976-18-01, FCC/1/1976-23-01, FCC/1/1976-25-01, FCC/1/1976-26-01, REI/1/0018-01-01, REI/1/4216-01-01, and URF/1/4098-01-01. This work was also supported by His Majesty Trust Funds at the Sultan Qaboos University, study code SR/MED/GENT/16/01.

PY - 2020/11/25

Y1 - 2020/11/25

N2 - We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.

AB - We have previously described a heart-, eye-, and brain-malformation syndrome caused by homozygous loss-of-function variants in SMG9, which encodes a critical component of the nonsense-mediated decay (NMD) machinery. Here, we describe four consanguineous families with four different likely deleterious homozygous variants in SMG8, encoding a binding partner of SMG9. The observed phenotype greatly resembles that linked to SMG9 and comprises severe global developmental delay, microcephaly, facial dysmorphism, and variable congenital heart and eye malformations. RNA-seq analysis revealed a general increase in mRNA expression levels with significant overrepresentation of core NMD substrates. We also identified increased phosphorylation of UPF1, a key SMG1-dependent step in NMD, which most likely represents the loss of SMG8--mediated inhibition of SMG1 kinase activity. Our data show that SMG8 and SMG9 deficiency results in overlapping developmental disorders that most likely converge mechanistically on impaired NMD.

UR - http://hdl.handle.net/10754/666138

UR - https://linkinghub.elsevier.com/retrieve/pii/S0002929720304043

U2 - 10.1016/j.ajhg.2020.11.007

DO - 10.1016/j.ajhg.2020.11.007

M3 - Article

C2 - 33242396

SN - 0002-9297

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

ER -

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

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