Michael Field, Patrick S

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Mutations in the BRWD3 Gene Cause X-Linked Mental Retardation Associated with Macrocephaly Michael Field, Patrick S. Tarpey, Raffaella Smith, Sarah Edkins, Sarah O’Meara, Claire Stevens, Calli Tofts, Jon Teague, Adam Butler, Ed Dicks, Syd Barthorpe, Gemma Buck, Jennifer Cole, Kristian Gray, Kelly Halliday, 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, Richard Wooster, Jenny Moon, Ying Luo, Helen Hughes, Marie Shaw, Kathryn L. Friend, Mark Corbett, Gillian Turner, Michael Partington, John Mulley, Martin Bobrow, Charles Schwartz, Roger Stevenson, Jozef Gecz, Michael R. Stratton, P. Andrew Futreal, F. Lucy Raymond The American Journal of Human Genetics Volume 81, Issue 2, Pages 367-374 (August 2007) DOI: 10.1086/520677 Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 1 Family pedigrees. A blackened symbol indicates the presence of mental retardation; a horizontal bar above a symbol indicates that DNA was collected and analyzed. The American Journal of Human Genetics 2007 81, 367-374DOI: (10.1086/520677) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 2 Clinical photography of families 322 and 336. a and b, Subject III-6 of family 322, aged 17 years. c, Subject II-11 of family 322. d and e, Brothers from family 336, aged 13 and 9 years. Note similar facial features, including prominent forehead; large, prominent ears; and pointed chin. The American Journal of Human Genetics 2007 81, 367-374DOI: (10.1086/520677) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3 Mutation analysis of BRDW3. a, DNA-sequence chromatograms showing the mutations in BRWD3 in genomic DNA from families 322, 336, and 328. The position of the mutation is indicated with an arrow. Control and affected-male sequence analyses are shown. b, RT-PCR analysis of the BRWD3 gene on lymphocyte RNA of proband III-6 from family 322 (blackened square) and a control individual (unblackened square). Primer sequences and conditions are available on request. M indicates pUC19/HpaII size marker, and plus (+) and minus (−) signs indicate the presence or absence of reverse transcriptase, respectively. c, Schematic diagrams showing BRWD3 splicing in a control individual (unblackened square) and patient III-6 from family 322 (blackened square) with the c.3325+1G→T mutation. The mutation results in aberrant splicing—that is, exclusion of exon 29 (dark gray) from the mature BRWD3 mRNA. The percentages given show exon 29 5′ splice-site consensus strength with and without the c.3325+1G→T mutation. In panel d, the sequence resulting from the splice-site mutation is illustrated in red, and the control cDNA sequence is in black. e, Sequence chromatogram of the BRWD3 RT-PCR product of patient III-6, showing the absence of exon 29 from the mRNA. The American Journal of Human Genetics 2007 81, 367-374DOI: (10.1086/520677) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 4 Protein alignments of vertebrate BRWD3 orthologues. Only partial sequences, corresponding to the human BRWD3 protein p.1551–1611, are shown. The lysine (K) residue at position 1596 is conserved, as indicated by an arrow. The amino acid residues that do not match the consensus sequence are highlighted with black boxes. The American Journal of Human Genetics 2007 81, 367-374DOI: (10.1086/520677) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 5 Schematic representation of the four predicted major isoforms of BRWD3. The amino terminus is to the left of the image. The WD40-repeat region is indicated by boxes marked with horizontal lines, and the bromodomains are indicated by the boxes marked with diagonal lines. The positions of the mutations relative to the translated products are indicated by arrows. The American Journal of Human Genetics 2007 81, 367-374DOI: (10.1086/520677) Copyright © 2007 The American Society of Human Genetics Terms and Conditions