Exome Sequencing Identifies CCDC8 Mutations in 3-M Syndrome, Suggesting that CCDC8 Contributes in a Pathway with CUL7 and OBSL1 to Control Human Growth

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Exome Sequencing Identifies CCDC8 Mutations in 3-M Syndrome, Suggesting that CCDC8 Contributes in a Pathway with CUL7 and OBSL1 to Control Human Growth Dan Hanson, Philip G. Murray, James O'Sullivan, Jill Urquhart, Sarah Daly, Sanjeev S. Bhaskar, Leslie G. Biesecker, Mars Skae, Claire Smith, Trevor Cole, Jeremy Kirk, Kate Chandler, Helen Kingston, Dian Donnai, Peter E. Clayton, Graeme C.M. Black The American Journal of Human Genetics Volume 89, Issue 1, Pages 148-153 (July 2011) DOI: 10.1016/j.ajhg.2011.05.028 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Mutations in CCDC8 Cause 3-M Syndrome (A) Individuals with 3-M syndrome who have CCDC8 mutations: i) 3M-2, ii) 3M-5. Their phenotype is indistinguishable from individuals with CUL7 or OBSL1 mutations. (B) Region of homozygosity on chromosome 19 common to three affected consanguineous individuals from different families. Analysis of SNP data from the Affymetrix Genome-Wide Human SNP Array 6.0 was performed by AutoSNPa. Black and yellow bars indicate homozygous and heterozygous SNP calls, respectively. Isolated heterozygous SNP calls within the larger homozygous region are likely to correspond to missed calls. The region of common homozygosity is flanked by recombinants at rs535840 located at 45,373,227 bp and rs1991722 located at 53,270,701 bp, as shown by the red boxes. (C) Schematic of the third 3-M syndrome critical region and identity of CCDC8 mutations. Shown is a genetic map of chromosome 19 highlighting the critical region located between rs535840 and rs1991722 and the relative location of CCDC8 within the region. CCDC8 is a single-exon gene encoding a protein of 538 amino acids, and bioinformatic analysis has indicated a coiled-coil domain located between residues 349–369 and 513–535 and an alanine-rich domain located between residues 299 and 471. Location and chromatograms of mutations in CCDC8 in individuals with 3-M syndrome are indicated by arrows. The American Journal of Human Genetics 2011 89, 148-153DOI: (10.1016/j.ajhg.2011.05.028) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 Molecular Characterization of CCDC8 (A) Immunoblot analysis of CCDC8 reveals loss of CCDC8 in an individual with 3-M syndrome and a CCDC8 mutation. HEK293 cells were transfected with a CCDC8 clone 24 hr before harvesting for both cytoplasmic and nuclear fractions. Human skin fibroblasts from controls and individuals with 3-M syndrome who have CUL7, OBSL1, or CCDC8 mutations were also harvested for cytoplasmic and nuclear fractions via standard protocols. Direct immunoblotting was performed for CCDC8 (Abnova) and loading was controlled by GAPDH (Santa-Cruz), demonstrating that individuals with 3-M syndrome who have either CUL7 or OBSL1 mutations have normal levels of CCDC8, whereas CCDC8 was undetectable in individual 3M-2. (B) RT-PCR of CCDC8 and GAPDH in a variety of adult tissues. The FirstChoice Human Total RNA Survey Panel (Ambion) was used for assessing CCDC8 expression in 20 different human tissues; CCDC8 mRNA was expressed widely but with low levels in spleen, skeletal muscle, small intestine, kidney, and liver. (C) Characterization of interactions among CUL7, OBSL1, and CCDC8. Immunoprecipitation analysis of the interactions between Myc-tagged CUL7 and V5-tagged OBSL1, V5-tagged OBSL1 and CCDC8, and CUL7 and CCDC8 in HEK293 cells. Plasmids expressing Myc-tagged CUL7, V5-tagged-OBSL1, and CCDC8 were used for transfection of HEK293 cells. The presence of recombinant proteins in each indicated transfection set was determined by direct immunoblot analysis of protein extracts. Interactions between Myc-tagged CUL7 and V5-tagged OBSL1, V5-tagged OBSL1 and CCDC8, and CUL7 and CCDC8 variants were analyzed by immunoprecipitation of extracts from each indicated transfection set with antibodies against V5 (AbDSerotec), c-Myc (Santa-Cruz), CUL7 (Santa-Cruz), or CCDC8 (Abnova), followed by capture with magnetic Dynabeads (Invitrogen). The precipitates were analyzed by immunoblotting with specific antibodies. The American Journal of Human Genetics 2011 89, 148-153DOI: (10.1016/j.ajhg.2011.05.028) Copyright © 2011 The American Society of Human Genetics Terms and Conditions