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

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Mutations in SMG9, Encoding an Essential Component of Nonsense-Mediated Decay Machinery, Cause a Multiple Congenital Anomaly Syndrome in Humans and Mice Ranad Shaheen, Shams Anazi, Tawfeg Ben-Omran, Mohammed Zain Seidahmed, L. Brianna Caddle, Kristina Palmer, Rehab Ali, Tarfa Alshidi, Samya Hagos, Leslie Goodwin, Mais Hashem, Salma M. Wakil, Mohamed Abouelhoda, Dilek Colak, Stephen A. Murray, Fowzan S. Alkuraya The American Journal of Human Genetics Volume 98, Issue 4, Pages 643-652 (April 2016) DOI: 10.1016/j.ajhg.2016.02.010 Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 1 Identification of an Autosomal-Recessive Multiple Congenital Anomalies Syndrome (A) Pedigrees of the two study families showing the consanguineous nature of the parents. The index individual is indicated in each pedigree by an arrow, and asterisks denote individuals whose DNA was available for analysis. (B) CT scan for the index individual in family 1 (IV:5) showing cerebellar vermis hypoplasia. (C and D) Facial images of the index individual in family 2 (V:1) showing a right-sided cleft lip (status post repair), a full and everted lower lip, a widow’s peak, hypertelorism, small eyes, posteriorly rotated ears with attached lobules, and a broad nasal bridge. The American Journal of Human Genetics 2016 98, 643-652DOI: (10.1016/j.ajhg.2016.02.010) Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 2 A Multiple Congenital Anomalies Syndrome Is Linked to SMG9 Mutations (A) AgileMultiIdeogram showing a single homozygous region, on chromosome 19, shared between the three affected individuals from the two families as indicated by the dark blue bars boxed in red. (B) Upper panel: schematic representation of SMG9 transcript (red triangles indicate the sites of the two mutations). Lower panel: sequence chromatograms of two variants in SMG9 identified in the family (control tracing is shown for comparison and the location of the mutation is denoted by red stars). (C) RT-PCR gel image and sequence chromatogram show the enhancement of aberrant SMG9 transcript in lymphoblasts derived from affected individual (Aff) as compared with lymphoblasts from a healthy individual of similar age (control), and the absence of the normal SMG9 transcript. (D) Relative quantitative real-time PCR showing 50% reduction in SMG9 expression in the affected individual in comparison to expression in the control individual. Result is the average for three independent experiments and three control individuals (p < 0.03 on t test). (E) Immunoblotting with antibody against the N terminal of SMG9 (SAB2107730) showing no detectable band from cells derived from the index individual (Aff) (target mass KDa, 57.7, 54.8) as compared with those derived from the three normal control individuals (Ct1, Ct2, Ct3), as well as the absence of the truncated SMG9 isoform at 22 KDa. The American Journal of Human Genetics 2016 98, 643-652DOI: (10.1016/j.ajhg.2016.02.010) Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 3 Global Transcriptional Changes Associated with SMG9 Deficiency (A) Heat-map of genes that were significantly dysregulated in a SMG9-deficient individual in comparison to three control individuals. The hierarchical clustering clearly distinguished individuals as either affected or controls. The expression level of each gene across the samples is scaled to [-3, 3] interval. These mapped expression levels are depicted with a color scale as shown at the bottom of the figure, such that highly expressed genes are indicated in red, intermediate in black, and weakly expressed in green. (B) GO and functional analysis of DE genes (up- or downregulated). x axis indicates the significance (−log p value) of the functional association that is dependent on the number of genes in a class as well as biological relevance. Dark bars represent upregulated genes, and light bars represent downregulated genes. The threshold line represents a p value of 0.05. The American Journal of Human Genetics 2016 98, 643-652DOI: (10.1016/j.ajhg.2016.02.010) Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 4 Generation of an Smg9 Null Allele (A) Schematic of mouse Smg9, showing the position of the CRISPR guide position in exon 2 (first coding exon; exon numbers indicated above the gene model). The mutant allele chosen for analysis contains a 2 bp deletion and simultaneous 10 bp insertion, resulting in a frameshift mutation beginning at 7:24403443 (GRCm38/mm10). (B) Sequence chromatogram of a TOPO-TA clone of the mutant allele (top) and a heterozygous mutant (bottom), confirming the allele structure. Red box indicates inserted sequence. (C) Structure of the predicted protein product showing the frameshift at residue 16 and the predicted premature termination at position 104. The aligned human protein is shown above the mouse sequence. (D) SMG9 phylogenetic tree and conservation across species. The American Journal of Human Genetics 2016 98, 643-652DOI: (10.1016/j.ajhg.2016.02.010) Copyright © 2016 The American Society of Human Genetics Terms and Conditions

Figure 5 Multiple Developmental Abnormalities in Smg9−/− Mouse Embryos (A–D) Mutant embryos at E15.5 display multiple developmental defects, including exencephaly (C) and sporadic hemorrhage and edema (D), versus wild-type (A) or heterozygous (B) littermates. (E–J) Volume slices of iodine-contrast microCT images of the mutant in (D) show multiple defects, including abnormal brain development (arrow, H), microphthalmia (arrow, I), and an atrioventricular septal defect and thin myocardium (arrow, J). Clear edema in the mutant images is indicated by the arrowheads (H–J). Control E15.5 sections from similar planes are shown in (E)–(G). (K–S) Some embryos survived or were recovered dead at E18.5 (L and M versus K). As with earlier stages, both mutants were developmentally delayed and showed a variable degree of edema. One mutant had anophthalmia of one eye (arrow in M and R). MicroCT images of the mutant in (M) show edema (arrowheads in R and S), a severely malformed brain (Q), and abnormally thin myocardium in (S). Control sections through similar planes are shown in (N)–(P). Scale bars for (E)–(J) are 0.5 mm (E and H) and 1.0 mm (F, G, I, and J) and for (N)–(S) are 1.0 mm (N, O, Q, and R) and 2.0 mm (P and S). The American Journal of Human Genetics 2016 98, 643-652DOI: (10.1016/j.ajhg.2016.02.010) Copyright © 2016 The American Society of Human Genetics Terms and Conditions