Identification of CC2D2A as a Meckel Syndrome Gene Adds an Important Piece to the Ciliopathy Puzzle Jonna Tallila, Eveliina Jakkula, Leena Peltonen,

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Identification of CC2D2A as a Meckel Syndrome Gene Adds an Important Piece to the Ciliopathy Puzzle Jonna Tallila, Eveliina Jakkula, Leena Peltonen, Riitta Salonen, Marjo Kestilä The American Journal of Human Genetics Volume 82, Issue 6, Pages 1361-1367 (June 2008) DOI: 10.1016/j.ajhg.2008.05.004 Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 1 Two MKS6 Fetuses with Typical Features (A and B) An ultrasound scan of case 3 (Table 1) at the 14th week of gestation. The biparietal measure is 2.46 cm and the occipital encephalocele (E) 1.60 cm in diameter (A). The kidneys (K) are grossly enlarged already with clearly visible cysts. The thorax is shallow and the lungs (L) are small (B). Ultrasound pictures courtesy of Pirkko Ämmalä. (C–E) Fetus aborted at 15th week of gestation (case 4). Distended stomach because of enlarged kidneys and polydactyly of the hands can be seen in (C), occipital encephalocele in (D), and polydactyly of the feet in (E). Exceptionally, this fetus also has hallux duplex, which is rarely seen in MKS fetuses. The American Journal of Human Genetics 2008 82, 1361-1367DOI: (10.1016/j.ajhg.2008.05.004) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 2 The MKS6 Candidate Region on Chromosome 4 Horizontal lines show the homozygous regions found in six affected MKS fetuses. The candidate region (chr4: 14,909,996-15,475,912, UCSC 2006) contained five genes of which CC2D2A was suggested to have a function in cilia. The fact that the overlapping homozygous region shared by the patients carrying the MKS6 mutation was only 565 kb and 63 SNPs in length gives us an estimation of the region size that could be used in search of genes for both recessive and complex diseases. The American Journal of Human Genetics 2008 82, 1361-1367DOI: (10.1016/j.ajhg.2008.05.004) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 3 Mutation Analysis and Structure of CC2D2A (A) Normal cDNA sequence from a control and the cDNA sequence from an affected fetus with the 4 base pair deletion (c.1761-1764) that is located in the end of exon 16. (B) Genomic sequence of the exon-intron boundary from a control, an affected fetus, and a heterozygous parent. In DNA of the affected fetus, the C→T substitution (c.1762C→T) creates a new splice site leading to the abnormal splicing as seen in (A). Red circles show the splice donor sites in the control's and patient's DNAs. (C) The gene structure of CC2D2A shows that translation starts from exon 3 and the new exon (marked by a red circle) is located after exon 29. The American Journal of Human Genetics 2008 82, 1361-1367DOI: (10.1016/j.ajhg.2008.05.004) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 4 Immunofluorescence Staining of Centrioles and Cilia Centrioles can be visualized with γ-tubulin staining in fibroblast cells of a patient (A) and a healthy control (B) (magnification 100×). Staining with acetylated tubulin shows that cilia are missing in the patient cells (C) but can be observed in control cells (D) (white arrows, magnification 63×). Scale bar represents 10 μm. The American Journal of Human Genetics 2008 82, 1361-1367DOI: (10.1016/j.ajhg.2008.05.004) Copyright © 2008 The American Society of Human Genetics Terms and Conditions