Asaf Ta-Shma, Tahir N. Khan, Asaf Vivante, Jason R

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Mutations in TMEM260 Cause a Pediatric Neurodevelopmental, Cardiac, and Renal Syndrome Asaf Ta-Shma, Tahir N. Khan, Asaf Vivante, Jason R. Willer, Pavle Matak, Chaim Jalas, Ben Pode-Shakked, Yishay Salem, Yair Anikster, Friedhelm Hildebrandt, Nicholas Katsanis, Orly Elpeleg, Erica E. Davis The American Journal of Human Genetics Volume 100, Issue 4, Pages 666-675 (April 2017) DOI: 10.1016/j.ajhg.2017.02.007 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Homozygous Truncating Mutations in TMEM260 Result in a Reduction of the Canonical Transcript (A) Two unrelated consanguineous pedigrees affected by TMEM260 mutations. Family 1 (left) has three affected individuals (1-II-1, 1-II-2, and 1-II-3) who harbor a homozygous TMEM260 truncating mutation that segregates with disease (c.1393C>T [p.Gln465∗]). Five healthy siblings are either wild-type (WT) or heterozygous for the mutation (M). A single affected individual (2-II-4) from an unrelated pedigree (family 2) has a homozygous truncating mutation in TMEM260 (c.1698_1701del [p.Tyr567Thrfs∗27]). Affected individuals are indicated with filled squares (male) and circles (female), unaffected individuals are indicated by unfilled squares (male) and circles (female), and diagonal lines indicate deceased individuals. (B) Schematic of the human TMEM260 locus shows the position of the two truncating mutations found in families 1 and 2. TMEM260 has two protein-coding isoforms (long [top] and short [bottom]), but both mutations affect only the long isoform. c.1393C>T is located in exon 11 of the long transcript but is not present in the short transcript. c.1698_1701del (p.Tyr567Thrfs∗27) is in the protein-coding part of the long transcript but in the 3′ UTR of the short transcript. (C and D) RT-PCR analyses of TMEM260 across eight different human tissues (Clontech Human MTC Panel I) (C) and a mixture of 35 different human tissues pooled from various developmental stages (Clontech Human Universal QUICK-Clone II) (D) show the presence of the long transcript (sequence confirmed) when amplified with primers located in exons 1 and 16 of the annotated long transcript. In contrast, amplification with primers F1 and R1 (located in exons 10 and 14, respectively) shows the presence of both long and short transcripts (sequence confirmed). GAPDH was used to control for RNA integrity. (E) Qualitative RT-PCR analysis from a lymphocyte cell line established from individual 1-II-3 and a primary fibroblast cell line isolated from individual 2-II-4 shows less expression of the long transcript than in the control, whereas the short transcript remains unaffected. Agarose gel images are shown; F1, F2, and R1 are the primers (located in exons 10, 11, and 14, respectively) depicted in (B), and GAPDH was used to control for RNA integrity. (F) qPCR (40 cycles of amplification) from the lymphoblastoid cell line of individual 1-II-3 shows significantly less expression (∼5-fold reduction; p = 0.001) of the long TMEM260 transcript than in lymphoblast control 1; this is rescued by the addition of emetine to the culture medium (∼3-fold increase; p = 0.006 versus individual 1-II-3). qPCR from a fibroblast cell line of individual 2-II-4 shows less expression (∼2-fold reduction; p = 0.05) of the long TMEM260 long than in fibroblast control 1. Experiments were performed in triplicate and normalized to GAPDH expression. The American Journal of Human Genetics 2017 100, 666-675DOI: (10.1016/j.ajhg.2017.02.007) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Suppression and Mutation of tmem260 Results in CNS Defects (A) Acetylated tubulin staining of WT (ZDR strain) larvae shows brain structures at 3.5 dpf (dorsal view). MOs (second from left) show fewer intertectal neurons (arrow) and smaller optic tecta size (dotted oval). (B and C) Co-injection of tmem260 translation-blocking MO and WT long TMEM260 mRNA rescues intertectal neuron count (B; see zoomed images in the second row of A) and optic tecta size. Co-injection of tmem260 MO and WT short TMEM260 mRNA rescues intertectal neuron count (B) and optic tecta size (C) but less significantly than co-injection of MO and WT long TMEM260 mRNA (n = 52–74 larvae per batch, repeated). Co-injection of tmem260 MO and WT long TMEM260 mRNA harboring c.1698_1701del does not rescue intertectal neuron count (B) or optic teca size (C) (n = 37–39 larvae per batch, repeated). (D and E) CRISPR/Cas9 F0 mutants (A: sixth and seventh from left) show significantly fewer intertectal neurons (D) and smaller optic tecta size (E). G2, G3, and G4 are CRISPR guide RNAs 2, 3, and 4, respectively. n = 48 larvae per batch, repeated. ∗∗∗p < 0.0001; ns, not significant (Student’s t test). Error bars indicate SEM. The American Journal of Human Genetics 2017 100, 666-675DOI: (10.1016/j.ajhg.2017.02.007) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 Truncation of TMEM260 Inhibits Proper Localization to Cellular Membranes (A) Predicted structure of the long and short forms of TMEM260, including the arrangement of domains. (B) Immunostaining of Neuro2A cells transfected with TMEM260 c-Myc-tagged long (top) and short (bottom) isoforms. (C) Immunoblot (left) and Ponceau S loading control (right) show the relative concentration of c-Myc-tagged long (87 kDa) and short (52 kDa) isoforms of TMEM260 in the membrane lysates (as indicated by Na+/K+ ATPase IB; bottom) of transiently transfected Neuro2A cells. The American Journal of Human Genetics 2017 100, 666-675DOI: (10.1016/j.ajhg.2017.02.007) Copyright © 2017 American Society of Human Genetics Terms and Conditions