CC2D2A, Encoding A Coiled-Coil and C2 Domain Protein, Causes Autosomal- Recessive Mental Retardation with Retinitis Pigmentosa Abdul Noor, Christian Windpassinger,

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CC2D2A, Encoding A Coiled-Coil and C2 Domain Protein, Causes Autosomal- Recessive Mental Retardation with Retinitis Pigmentosa Abdul Noor, Christian Windpassinger, Megha Patel, Beata Stachowiak, Anna Mikhailov, Matloob Azam, Muhammad Irfan, Zahid Kamal Siddiqui, Farooq Naeem, Andrew D. Paterson, Muhammad Lutfullah, John B. Vincent, Muhammad Ayub The American Journal of Human Genetics Volume 82, Issue 4, Pages 1011-1018 (April 2008) DOI: 10.1016/j.ajhg.2008.01.021 Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree Showing Three Branches of the Family from Mianwali District, Punjab Province, Pakistan Filled symbols indicate individuals affected with mental retardation. The quarter-filled symbol, highlighted within a red box, indicates the patient with mental retardation but subsequently determined to have tetrasomy X. The American Journal of Human Genetics 2008 82, 1011-1018DOI: (10.1016/j.ajhg.2008.01.021) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 2 Ideogrammatic Representation of the Mutation Region on 4p15.33 (A) Position of the 11.2 Mb common homozygous stretch on 4p15. and the organization of various known genes within this region. (B) The intron 19 donor splice-site mutation sequence, with wild-type, followed by carrier (heterozygote) sequence and the homozygous mutation from affected individuals. (C) The genomic organization of CC2D2A and the consequence of the mutation, namely the splicing out of exon 19, which results in a shift of reading frame leading to 13 nonsense amino acids followed by a stop codon, thus prematurely truncating the protein at this point. Sequence analysis was performed with BigDye Terminator v3.1 Cycle Sequencing (Applied Biosystems). The American Journal of Human Genetics 2008 82, 1011-1018DOI: (10.1016/j.ajhg.2008.01.021) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 3 Haplotype Analysis Markers are shown in red, and haplotypes within a red box indicate the disease haplotype shared between affected individuals (homozygous) and carriers (heterozygous). The American Journal of Human Genetics 2008 82, 1011-1018DOI: (10.1016/j.ajhg.2008.01.021) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 4 Tissue Transcription Analysis of CC2D2A RT-PCR expression analysis with a multiple-tissue panel of normalized first-strand cDNA (Clontech) for CC2DA (top) and housekeeping gene G3PDH, which was run as a control (bottom). For RT-PCR amplification, we used a forward primer from exon 18 (5′-ACAGTCAGTCGGCCACTAGG-3′) and a reverse primer from exon 25 (5′- GTTCTGCCAGCTTGAAAAGG-3′) with PCR product size of 963 bp. A 100 bp size ladder is shown to the left. The American Journal of Human Genetics 2008 82, 1011-1018DOI: (10.1016/j.ajhg.2008.01.021) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 5 Comparative Protein Sequence Analysis of CC2D2A Boxshade alignments for (A) a section of the C2 domain (residues 1099 to 1202 of the human protein) and (B) a section of the C-terminal region (1280–1463). A selection of sequences from 11 representative species (out of 18 studied) across the evolutionary spectrum are shown. Alignment with the C-terminal region of the human paralogue, CC2D2B, is also shown; however, no homology was detected with the C2 region. The upstream half of the C2 region is not shown because sections of this region are not present in some lower-order vertebrates and nonvertebrates. Also, only a portion of the C-terminal region is shown, for the sake of succinctness. Residues that were conserved across all 18 species analyzed (including those not included in the figure: chimp, horse, cow, rat, tetraodon, zebrafish, and Drosophila) are marked with an asterisk. Accession numbers for sequences used are as follows in parentheses: chimpanzee (XM_526530), rhesus monkey (XM_001118936), horse (XM_001500638), cow (UPI0000F333EB), dog (UPI0000EB4478), mouse (NM_172274), rat (XM_001055728), opossum (XM_001369737), chicken (XM_420777), Xenopus (BC077972), zebrafish (XM_693709), fugu (NEWSINFRUT00000150241), tetraodon (GSTENT00032796001), sea urchin (XM_775975), fruitfly (NM_137386), mosquito (XM_001658220), and nematode (NM_059625). The American Journal of Human Genetics 2008 82, 1011-1018DOI: (10.1016/j.ajhg.2008.01.021) Copyright © 2008 The American Society of Human Genetics Terms and Conditions