Mutations in ZDHHC9, Which Encodes a Palmitoyltransferase of NRAS and HRAS, Cause X-Linked Mental Retardation Associated with a Marfanoid Habitus F.

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Mutations in ZDHHC9, Which Encodes a Palmitoyltransferase of NRAS and HRAS, Cause X-Linked Mental Retardation Associated with a Marfanoid Habitus F. Lucy Raymond, Patrick S. Tarpey, Sarah Edkins, Calli Tofts, Sarah O’Meara, Jon Teague, Adam Butler, Claire Stevens, Syd Barthorpe, Gemma Buck, Jennifer Cole, Ed Dicks, Kristian Gray, Kelly Halliday, Katy Hills, Jonathon Hinton, David Jones, Andrew Menzies, Janet Perry, Keiran Raine, Rebecca Shepherd, Alexandra Small, Jennifer Varian, Sara Widaa, Uma Mallya, Jenny Moon, Ying Luo, Marie Shaw, Jackie Boyle, Bronwyn Kerr, Gillian Turner, Oliver Quarrell, Trevor Cole, Douglas F. Easton, Richard Wooster, Martin Bobrow, Charles E. Schwartz, Jozef Gecz, Michael R. Stratton, P. Andrew Futreal The American Journal of Human Genetics Volume 80, Issue 5, Pages 982-987 (May 2007) DOI: 10.1086/513609 Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of families with XLMR and mutations in ZDHHC9. Individuals marked with an asterisk (*) carry the mutant allele in each family. Carrier females who have been shown to be heterozygous for the wild-type allele and the mutation are labeled “het.” Representative sequence chromatograms of wild-type and mutant sequences are shown below each pedigree. n.a. = no sample was available for testing; wt = wild-type sequence. The American Journal of Human Genetics 2007 80, 982-987DOI: (10.1086/513609) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 2 a, RT-PCR analysis of the ZDHHC9 gene by use of lymphocyte RNA from an affected male individual in family 602 and an unaffected control. A 547-bp PCR product was identified from cDNA made from control cells containing sequence from exons 2–4, by use of the predicted splice junctions. In family 602, only a 407-bp PCR product was identified. b, Diagram of the cDNA detected in family 602, which included an upstream splice-donor site, resulting in the loss of 140 bp at the terminus of exon 2, and the sequence chromatogram of the novel splicing event, leading to the mutation. c, Effect of the upstream splice-donor site within exon 2 spliced to exon 3. This results in a frameshift and truncated protein p.T11fsX33. The American Journal of Human Genetics 2007 80, 982-987DOI: (10.1086/513609) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3 Sequence alignment of the conserved palmitoyltransferase active site of proteins ZDHHC9, ZDHHC14, and ZDHHC5 in multiple species (Homo sapiens, Canis familiaris, Mus musculus, Gallus gallus, Danio rerio, Xenopus laevis, Tetraodon nigroviridis, Drosophila melanogaster, Caenorhabditis elegans, Neurospora crassa, and Saccharomyces cerevisiae). Sequence alignment was performed using ClustalW. Conserved amino acid residues are highlighted in yellow, and the two missense mutations are identified in red. The American Journal of Human Genetics 2007 80, 982-987DOI: (10.1086/513609) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 4 a, Diagrammatic representation of the exon structure of ZDHHC9, with positions of mutations found in families with XLMR. Exons that are translated are indicated by yellow shading. b, Diagrammatic representation of the protein ZDHHC9, with the palmitoyltransferase domain indicated by green shading. The location of the amino acid changes in the protein due to mutations in ZDHHC9 are indicated by arrows. The family numbers are in parentheses. The American Journal of Human Genetics 2007 80, 982-987DOI: (10.1086/513609) Copyright © 2007 The American Society of Human Genetics Terms and Conditions