Short Stature, Onychodysplasia, Facial Dysmorphism, and Hypotrichosis Syndrome Is Caused by a POC1A Mutation Ofer Sarig, Sagi Nahum, Debora Rapaport,

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Short Stature, Onychodysplasia, Facial Dysmorphism, and Hypotrichosis Syndrome Is Caused by a POC1A Mutation Ofer Sarig, Sagi Nahum, Debora Rapaport, Akemi Ishida-Yamamoto, Dana Fuchs-Telem, Li Qiaoli, Ksenya Cohen-Katsenelson, Ronen Spiegel, Janna Nousbeck, Shirli Israeli, Zvi-Uri Borochowitz, Gilly Padalon-Brauch, Jouni Uitto, Mia Horowitz, Stavit Shalev, Eli Sprecher The American Journal of Human Genetics Volume 91, Issue 2, Pages 337-342 (August 2012) DOI: 10.1016/j.ajhg.2012.06.003 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Linkage and PCR-RFLP Analyses of Two Families Affected by SOFT Syndrome The family trees appear in the upper panel (black symbols denote affected individuals carrying mutation c.512T>C in POC1A). Haplotype analysis with polymorphic markers in chromosomal region 3q21 is depicted in the middle panel and reveals a homozygous haplotype shared by all affected individuals (boxed in red). The lower panel depicts the PCR-RFLP (restriction fragment-length polymorphism) analysis: the c.512T>C substitution generates a recognition site for BtgI. Thus, unaffected individuals display a single fragment of 353 bp, individuals affected with SOFT syndrome show two fragments of 200 and 175 bp, and all three fragments are found in heterozygous carriers of the mutation. The American Journal of Human Genetics 2012 91, 337-342DOI: (10.1016/j.ajhg.2012.06.003) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Clinical Features of SOFT Syndrome (A) Affected individuals show a final height consistent with a height age of 6–8 years. (B) Affected individuals display typical facial features, including a long triangular face with a prominent nose and small ears. (C) Clinodactyly of the fifth finger, brachydactyly, and hypoplastic fingernails are noted. (D) Note sparse and short hair. The American Journal of Human Genetics 2012 91, 337-342DOI: (10.1016/j.ajhg.2012.06.003) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 Mutation Analysis (A) Sequence analysis of POC1A reveals a homozygous base substitution at cDNA position 512 (red arrow) in all affected individuals (lower panel). Healthy family members were found to be heterozygous carriers of the mutation (middle panel). The wild-type sequence is given for comparison (upper panel). (B) The mutation in POC1A is predicted to alter a highly conserved amino acid residue as indicated by conservation analysis made with the ConSurf Server. The L171 residue is indicated by a black arrow. The American Journal of Human Genetics 2012 91, 337-342DOI: (10.1016/j.ajhg.2012.06.003) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 4 Centrosome Amplification (A) Affected and healthy fibroblasts were fixed, stained for γ-tubulin (centrosomes) (Santa Cruz Biotechnology, Santa Cruz, CA, USA or Sigma-Aldrich, Saint Louis, MO, USA), and visualized by confocal microscopy. Nuclei were stained with DAPI. POC1A-mutant cells show significant amplification of centrosomes (>2/cell; arrows), which also appear to be in various shapes (sand like). Scale bars represent 5 μm and 10 μm. (B) The number of cells displaying an abnormal centrosome number (>2/cell) and morphology was determined by the examination of 130–250 randomly chosen cells stained with γ-tubulin antibodies. Results are provided as a percentage of abnormal cells out of the total number of cells counted ± standard error of the mean (SEM). Asterisks indicate statistical significance (∗∗∗p < 0.0001) as analyzed by the Student's t test. (C) Electron microscopic examination does not reveal significant differences between the ultrastructural appearances of centrioles (arrows) of affected and control cells. Scale bars represent 2 μm and 200 nm. The American Journal of Human Genetics 2012 91, 337-342DOI: (10.1016/j.ajhg.2012.06.003) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 5 Altered Golgi Morphology and Aberrant Trafficking to the Golgi in SOFT Syndrome Fibroblasts (A) SOFT syndrome fibroblasts and control fibroblasts were fixed and stained with GM130 antibodies (Sigma-Aldrich, Saint Louis, MO, USA). Arrows point to dispersed Golgi. Scale bars represent 10 μm and 20 μm. (B) Cells displaying a dispersed or typical perinuclear Golgi pattern were counted (150–250 randomly chosen cells stained with GM130 antibodies were counted for each experiment). Results are provided as a percentage of abnormal cells out of the total number of cells counted ± SEM. Asterisks indicate statistical significance (∗∗∗p < 0.0001) as analyzed by the Student's t test. (C) Cells were labeled with AlexaFluor 555-conjugated subunit B of cholera toxin (CTx-B; Invitrogen/Molecular Probes, Eugene, OR, USA) for the indicated times, fixed, and visualized by confocal microscopy. Arrows indicate normal transport of CTx-B to the Golgi, and arrowheads show atypical peripheral large vesicles representing abnormal CTx-B transport. The scale bar represents 20 μm. (D) Abnormal CTx-B trafficking was quantified after 1 hr and 3 hr pulse in 40–85 randomly chosen cells. Results are provided as a percentage of cells displaying abnormal transport out of the total number of cells counted ± SEM. Asterisks indicate statistical significance (∗∗∗p < 0.0001) as analyzed by the Student's t test. The American Journal of Human Genetics 2012 91, 337-342DOI: (10.1016/j.ajhg.2012.06.003) Copyright © 2012 The American Society of Human Genetics Terms and Conditions