The Primordial Growth Disorder 3-M Syndrome Connects Ubiquitination to the Cytoskeletal Adaptor OBSL1 Dan Hanson, Philip G. Murray, Amit Sud, Samia A.

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The Primordial Growth Disorder 3-M Syndrome Connects Ubiquitination to the Cytoskeletal Adaptor OBSL1 Dan Hanson, Philip G. Murray, Amit Sud, Samia A. Temtamy, Mona Aglan, Andrea Superti-Furga, Sue E. Holder, Jill Urquhart, Emma Hilton, Forbes D.C. Manson, Peter Scambler, Graeme C.M. Black, Peter E. Clayton The American Journal of Human Genetics Volume 84, Issue 6, Pages 801-806 (June 2009) DOI: 10.1016/j.ajhg.2009.04.021 Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Features of 3-M Syndrome Patients (A) A patient from family 3-M-6 aged 10 years. The facial appearance is characterized by fleshy tipped anteverted nares, full fleshy lips, triangular shaped face, midface hypoplasia, and prominent ears. These features become less prominent with increasing age. (B) The affected child from family 3-M-2 aged 10 months. Facial appearance is characterized by similar fleshy tipped anteverted nares, full fleshy lips, triangular shaped face, and midface hypoplasia seen in 3-M-6 but also distinct frontal bossing. Both had proportionate short stature. Prominent heels are seen in most patients and may be a useful diagnostic feature. Patient photographs and X-rays from two brothers from family 3-M-9 have previously been reported by Temtamy et al.3. The American Journal of Human Genetics 2009 84, 801-806DOI: (10.1016/j.ajhg.2009.04.021) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 2 Genetic Mapping of the Second 3-M Syndrome Locus (A) The region of common autozygosity shared between 3-M families 4 and 5 is located between rs966423 and rs1597167. (B) The identical haplotype shared between 3-M families 4–6 located between rs1516086 and rs10498071. (C) Exon and intron structure of OBSL1 with mutations identified in 10 3-M syndrome families and domain structure of each OBSL1 isoform. (D) Sequence traces of the OBSL1 mutations (i. families 2–7; ii. family 9) with corresponding wild-type sequences. The American Journal of Human Genetics 2009 84, 801-806DOI: (10.1016/j.ajhg.2009.04.021) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 3 OBSL1 Mutations Induce NMD and siRNA Knockdown of OBSL1 Results in Decreased CUL7 Expression (A) Western blot analysis of V5-tagged OBSL1 clones. Expression of N- or C-terminally tagged OBSL1 isoforms in HEK293 cells led to the detection of N-tagged isoforms (lanes 1 and 2) but not of C-tagged isoforms (lanes 3 and 4), demonstrating the expression of prematurely truncated isoforms. Wild-type protein tagged at either terminus was detected (lanes 5 and 6). (B) siRNA knockdown of OBSL1 in HEK293 cells via two different siRNAs (that target all three wild-type isoforms) resulted in the decreased expression of CUL7 (second from top, upper band [arrow], lower band represents nonspecific binding) but did not alter the expression of p53 (third from top). The bottom gel shows a GAPDH loading control. The American Journal of Human Genetics 2009 84, 801-806DOI: (10.1016/j.ajhg.2009.04.021) Copyright © 2009 The American Society of Human Genetics Terms and Conditions