Mutations in CUL4B, Which Encodes a Ubiquitin E3 Ligase Subunit, Cause an X-linked Mental Retardation Syndrome Associated with Aggressive Outbursts, Seizures,

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Mutations in CUL4B, Which Encodes a Ubiquitin E3 Ligase Subunit, Cause an X-linked Mental Retardation Syndrome Associated with Aggressive Outbursts, Seizures, Relative Macrocephaly, Central Obesity, Hypogonadism, Pes Cavus, and Tremor Patrick S. Tarpey, F. Lucy Raymond, Sarah O’Meara, Sarah Edkins, Jon Teague, Adam Butler, Ed Dicks, Claire Stevens, Calli Tofts, Tim Avis, Syd Barthorpe, Gemma Buck, Jennifer Cole, Kristian Gray, Kelly Halliday, Rachel Harrison, Katy Hills, Andrew Jenkinson, David Jones, Andrew Menzies, Tatiana Mironenko, Janet Perry, Keiran Raine, David Richardson, Rebecca Shepherd, Alexandra Small, Jennifer Varian, Sofie West, Sara Widaa, Uma Mallya, Jenny Moon, Ying Luo, Susan Holder, Sarah F. Smithson, Jane A. Hurst, Jill Clayton-Smith, Bronwyn Kerr, Jackie Boyle, Marie Shaw, Lucianne Vandeleur, Jayson Rodriguez, Rachel Slaugh, Douglas F. Easton, Richard Wooster, Martin Bobrow, Anand K. Srivastava, Roger E. Stevenson, Charles E. Schwartz, Gillian Turner, Jozef Gecz, P. Andrew Futreal, Michael R. Stratton, Michael Partington The American Journal of Human Genetics Volume 80, Issue 2, Pages 345-352 (February 2007) DOI: 10.1086/511134 Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 1. Families with mutations in CUL4B. Below the pedigree for each family, a wild-type (wt) and a mutant (mut) representative trace are shown. The position of the mutation is indicated by an arrow, and the numbering is according to reference sequences (GenBank accession numbers NM_003588 and NP_003579). The American Journal of Human Genetics 2007 80, 345-352DOI: (10.1086/511134) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 2. a, Schematic representation of the genomic structure of CUL4B, with positions of mutations found in eight families with XLMR. b, Schematic representation of the protein sequence. The cullin domain is marked, and the positions of the eight mutations are indicated. The American Journal of Human Genetics 2007 80, 345-352DOI: (10.1086/511134) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3. RT-PCR analysis. a, Analysis of family 329, demonstrating the skipping of exon 7 in the CUL4B transcript. b, Analysis of family 363, showing deletion of the terminal 80 bp of exon 20, which results from the activation of a cryptic splice-donor site upstream from the normal donor site. The American Journal of Human Genetics 2007 80, 345-352DOI: (10.1086/511134) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 4. Alignment of available CUL4B protein sequences, showing the conservation of amino acid residues altered by the missense mutations. Accession numbers in parentheses are from the Ensembl Genome Browser. The American Journal of Human Genetics 2007 80, 345-352DOI: (10.1086/511134) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 5. a, b, and d, Three half brothers from family 42 (pedigree designations IV-1, IV-2, and IV-3, respectively), aged 21, 18, and 15 years, respectively. c, Feet of IV-2, showing a wide sandal gap and small size. e and f, Individual IV-2 from family 43, at ages 4 mo (e) and 4 years (f). g, Features of an affected cousin, IV-4. h, i, and j, Individual IV-1 from family 363 at age 6 years, showing gynecomastia (h and i), and at age 13 years, showing splayed toes with a wide sandal gap (j). k, l, and m, Uncle (III-4) of IV-1 from family 363, showing central obesity (k), upper dorsal kyphosis (l), and micropenis (m). The American Journal of Human Genetics 2007 80, 345-352DOI: (10.1086/511134) Copyright © 2007 The American Society of Human Genetics Terms and Conditions