Michael R. Knowles, Margaret W. Leigh, Lawrence E

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Exome Sequencing Identifies Mutations in CCDC114 as a Cause of Primary Ciliary Dyskinesia Michael R. Knowles, Margaret W. Leigh, Lawrence E. Ostrowski, Lu Huang, Johnny L. Carson, Milan J. Hazucha, Weining Yin, Jonathan S. Berg, Stephanie D. Davis, Sharon D. Dell, Thomas W. Ferkol, Margaret Rosenfeld, Scott D. Sagel, Carlos E. Milla, Kenneth N. Olivier, Emily H. Turner, Alexandra P. Lewis, Michael J. Bamshad, Deborah A. Nickerson, Jay Shendure, Maimoona A. Zariwala The American Journal of Human Genetics Volume 92, Issue 1, Pages 99-106 (January 2013) DOI: 10.1016/j.ajhg.2012.11.003 Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 1 Cross-section Analysis of Ciliary Ultrastructure by Electron Microscopy and Segregation Analysis of CCDC114 (A) Normal ciliary ultrastructure from healthy subject (left) and absence of outer dynein arms (right) from UNC family 62 with biallelic mutations in CCDC114. (B–E) Pedigrees with mutations segregating in trans, consistent with autosomal-recessive mode of inheritance. The American Journal of Human Genetics 2013 92, 99-106DOI: (10.1016/j.ajhg.2012.11.003) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 2 Genomic Organization of CCDC114 and Location of PCD-Causing Mutations (A) The transcript of CCDC114 consists of 3,215 bp and encodes 670 amino acid protein. Filled box designates exons “E,” horizontal lines designate intron “IVS,” and location of 5′ UTR, 3′ UTR, and start and stop codons are shown. Introns/exons are not drawn to scale. The positions of all identified CCDC114 mutations are indicated. (B, D, and E) Heterozygous sequences in affected (bottom) and corresponding wild-type (top) sequences in controls. (C) Homozygous (bottom) and heterozygous (middle) sequences in affected and the corresponding wild-type sequences (top) in control. Base sequence, amino acid sequence, and codon numbers are shown. Intron-exon junctions are shown with the red dotted lines. The American Journal of Human Genetics 2013 92, 99-106DOI: (10.1016/j.ajhg.2012.11.003) Copyright © 2013 The American Society of Human Genetics Terms and Conditions

Figure 3 Expression Analysis via Reverse-Transcriptase PCR (A) Expression pattern of CCDC114 in a panel of normal human tissues. (B) Expression pattern of CCDC114 (top) during ciliogenesis in human airway cells. RNA was isolated from human airway epithelia cells at different times after plating on collagen-coated culture inserts at an air/liquid interface. Under these conditions the cells initially grow as a single monolayer of undifferentiated “basal-like” cells. After 10–14 days, ciliated cells begin to appear, increasing over the next 2–3 weeks before plateauing at approximately 60%–80% of the culture.21,22 For both expression analyses, DNAI1 (middle) was used as a known ciliary gene control and cyclophilin (bottom) as a positive RNA control. The American Journal of Human Genetics 2013 92, 99-106DOI: (10.1016/j.ajhg.2012.11.003) Copyright © 2013 The American Society of Human Genetics Terms and Conditions