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 - Publisher Copyright:
© 2020 American Society of Human Genetics
PY - 2020/12/3
Y1 - 2020/12/3
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.
KW - NMD
KW - RNA-seq
KW - SMG1C
KW - cataract
KW - congenital heart disease
KW - intellectual disability
KW - microcephaly
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U2 - 10.1016/j.ajhg.2020.11.007
DO - 10.1016/j.ajhg.2020.11.007
M3 - Article
C2 - 33242396
AN - SCOPUS:85097310432
SN - 0002-9297
VL - 107
SP - 1178
EP - 1185
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 6
ER -