Ciliary Abnormalities Due to Defects in the Retrograde Transport Protein DYNC2H1 in Short-Rib Polydactyly Syndrome Amy E. Merrill, Barry Merriman, Claire.

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Ciliary Abnormalities Due to Defects in the Retrograde Transport Protein DYNC2H1 in Short-Rib Polydactyly Syndrome Amy E. Merrill, Barry Merriman, Claire Farrington-Rock, Natalia Camacho, Eiman T. Sebald, Vincent A. Funari, Matthew J. Schibler, Marc H. Firestein, Zachary A. Cohn, Mary Ann Priore, Alicia K. Thompson, David L. Rimoin, Stanley F. Nelson, Daniel H. Cohn, Deborah Krakow The American Journal of Human Genetics Volume 84, Issue 4, Pages 542-549 (April 2009) DOI: 10.1016/j.ajhg.2009.03.015 Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 1 Radiographic Hallmarks of SRP (A) R01-314A, newborn. A/P view showing the characteristic trident pelvis (arrow) and the long narrow chest with horizontal ribs. (B) R01-314A, newborn. The arrow identifies the distal end of the femur, showing metaphyseal spikes. (C) R01-314A, newborn. There is no polydactyly in the hand (arrow). (D) R06-237A, 20 weeks gestation. The arrow identifies metaphyseal spikes of the distal humerus. (E) R00-097A, 20 weeks gestation. The arrow identifies the preaxial polydactyly of the foot. (F) R01-314B, 20 weeks gestation. The arrow identifies postaxial polydactyly of the foot. (G) R06-237A, 20 weeks gestation. The arrow identifies postaxial polydactyly of the foot. (H) R00-097A, 20 weeks gestation. The lower extremity shows a shortened femur, tibia, and fibula with metaphyseal spikes (arrow). The American Journal of Human Genetics 2009 84, 542-549DOI: (10.1016/j.ajhg.2009.03.015) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 2 Homozygosity by Descent Mapping (A) Homozygosity by descent mapping in family R01-314. All intervals of homozygosity shared among the four affected family members of family R01-314 are plotted across the genome. Chromosomal position is indicated on the x axis, and length of the homozygous interval is plotted on the y axis such that height of the filled-in graphic indicates the length of the measured homozygous intervals in centimorgans. Physical distances: chromosome 1 (rs11209979-rs4656100; 71,153,296-85,028,578bp), chromosome 11 (rs 10501715-rs1029278; 86,043.913-119,363,025bp), and chromosome 16 (rs12924823-rs12928078; 10,726,309-24,280,658bp). The American Journal of Human Genetics 2009 84, 542-549DOI: (10.1016/j.ajhg.2009.03.015) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 3 DYNC2H1 Mutation Analysis Sequencing chromatograms demonstrating mutations in DYNC2H1 in the three families studied: (A) R01-314, (B) R00-097, and (C) R06-237. (D) Diagram of the DYNC2H1 molecule with the locations of the protein sequence changes predicted by the mutations. The scale below indicates the length of the protein. AAA, ATP binding and hydrolysis domains; C domain, carboxyl-terminal domain; aa, amino acid. The American Journal of Human Genetics 2009 84, 542-549DOI: (10.1016/j.ajhg.2009.03.015) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 4 c. IVS33+1 G > T Allele Found in R06-237 Leads to Nonsense-Mediated Decay Sequencing chromatograms of RT-PCR products from R06-237A chondrocytes generated in the absence (A) and presence (B) of cycloheximide. (C) Quantitative PCR analysis showed an almost 50% reduction in DYNC2H1 transcripts in R06-237A chondrocytes compared to stage-matched control chondrocytes. Vertical bars indicate the standard deviation. The American Journal of Human Genetics 2009 84, 542-549DOI: (10.1016/j.ajhg.2009.03.015) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 5 p.R587C Allele Found in R01-314 Produces Abnormal Primary Cilia in Chondrocytes (A) Cilia visualized by scanning electron microscopy showed normally shaped cilia in control chondrocytes. The boxed area is shown at higher magnification in (C). (B) Cilia present on chondrocytes from case R01-314B were short and had an abnormal bulge at the tip of the axoneme. The boxed area is shown at higher magnification in (D). The American Journal of Human Genetics 2009 84, 542-549DOI: (10.1016/j.ajhg.2009.03.015) Copyright © 2009 The American Society of Human Genetics Terms and Conditions

Figure 6 SRP Chondrocytes Have Abnormal Primary Cilia and Increased Levels of Acetylated α-tubulin (A and D) Immunofluorescence for acetylated α-tubulin (red) and DAPI (blue) in primary chondrocytes shows normal presentation of cilia in control cells. Chondrocytes from R01-314B (B and E) and R06-237A (C and F) show abnormal cilia and increased amounts of cytoplasmic acetylated α-tubulin. (D–F) Higher-magnification views of the boxed regions in (A)–(C). Cilia length measured an average of 3.2 ± 0.57 μm in control cells and 1.9 ± 0.44 μm in SRP chondrocytes (p, 0.01, Student's t test). (G–I) Immunofluorescence for acetylated α-tubulin (red), γ tubulin (green), and DAPI (blue) shows the presence of a basal body in both control and SRP chondrocytes. (J) Immunoblot analysis of acetylated α-tubulin expression in control, R01-314A, and R06-237B chondrocytes showed an increase of acetylated α-tubulin expression in mutant chondrocytes compared to the control. β-actin was used as a protein loading control. (K) Quantitation of the ratio of acetylated α-tubulin relative to β-actin from the immunoblots (n = 4) demonstratied about a 2-fold increase in the relative level of acetylated α-tubulin in mutant chondrocytes compared to the normal control. Vertical bars indicate the standard deviation. The American Journal of Human Genetics 2009 84, 542-549DOI: (10.1016/j.ajhg.2009.03.015) Copyright © 2009 The American Society of Human Genetics Terms and Conditions