Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice

Abstract

Nonsense-mediated decay (NMD) is an important process that is best known for degrading transcripts that contain premature stop codons (PTCs) to mitigate their potentially harmful consequences, although its regulatory role encompasses other classes of transcripts as well. Despite the critical role of NMD at the cellular level, our knowledge about the consequences of deficiency of its components at the organismal level is largely limited to model organisms. In this study, we report two consanguineous families in which a similar pattern of congenital anomalies was found to be most likely caused by homozygous loss-of-function mutations in SMG9, encoding an essential component of the SURF complex that generates phospho-UPF1, the single most important step in NMD. By knocking out Smg9 in mice via CRISPR/Cas9, we were able to recapitulate the major features of the SMG9-related multiple congenital anomaly syndrome we observed in humans. Surprisingly, human cells devoid of SMG9 do not appear to have reduction of PTC-containing transcripts but do display global transcriptional dysregulation. We conclude that SMG9 is required for normal human and murine development, most likely through a transcriptional regulatory role, the precise nature of which remains to be determined.

Confirmation and further delineation of the SMG9‐deficiency syndrome, a rare and severe developmental disorder

“…The SMG9 gene encodes a major protein from the nonsense‐mediated decay (NMD) machinery (Fernández et al, ). The absence of Smg9 in mice resulted in the dysregulation of many transcripts (Shaheen et al, ). In contrast, there was no evidence of widespread perturbation of the degradation by the NMD of premature termination codon (PTC)‐containing transcripts.…”

“…Pangenomic next generation sequencing (NGS) techniques such as exome and genome sequencing are becoming central in the genetic exploration and diagnosis of patients with nonspecific or ultra‐rare diseases which cannot be identified clinically (Lee et al, ). SMG9 deficiency is such an ultra‐rare and largely unrecognizable developmental disorder, originally described in 2016 by Shaheen and collaborators (Shaheen et al, , p. 9). In this study, the authors investigated two families using autozygocity mapping, linkage analysis and exome sequencing, and identified a homozygous truncating variant in the SMG9 gene in affected individuals of both families.…”

Bi-allelic TMEM94 Truncating Variants Are Associated with Neurodevelopmental Delay, Congenital Heart Defects, and Distinct Facial Dysmorphism

“…20 To understand the effect of the truncating variants in TMEM94 on global gene expression, we performed gene expression microarray of one affected (Family 2-II.3) versus four gender matched healthy controls as previously described. 21 Significantly dysregulated genes were defined as those with absolute fold change (FC) > 1.5 and adjusted Welch's t test p value < 0.05.…”

Structure of a SMG8–SMG9 complex identifies a G-domain heterodimer in the NMD effector proteins

“…However, general impairment of NMD on natural PTC-containing targets was not detected in smg-8 mutants in C. elegans (Rosains and Mango 2012) and in human subjects carrying homozygous loss-of-function SMG9 mutations (Shaheen et al 2016). Human patients with SMG9 deficiency display widespread transcriptional dysregulation, suggesting a predominant role of SMG9 in post-transcriptional regulation rather than in surveillance (Shaheen et al 2016).…”