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Deletion in Cobalamin Synthetase W Domain-Containing Protein 1 Is Associated with Congenital Anomalies of the Kidney and Urinary Tract

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Deletion in Cobalamin Synthetase W Domain-Containing Protein 1 Is Associated with Congenital Anomalies of the Kidney and Urinary Tract Title Deletion in Cobalamin Synthetase W Domain-Containing Protein 1 is associated with congenital anomalies of the kidney and urinary tract Authors Shoichiro Kanda1,2, M.D., Ph.D., Masaki Ohmuraya3, M.D., Ph.D., Hiroyuki Akagawa4, M.D., Ph.D., Shigeru Horita5, Ph.D., Yasuhiro Yoshida1, M.D., Naoto Kaneko2, M.D., Noriko Sugawara2, M.D., Ph.D., Kiyonobu Ishizuka2, M.D., Kenichiro Miura2, M.D., Ph.D., Yutaka Harita1, M.D., Ph.D., Toshiyuki Yamamoto4,6, M.D., Ph.D., Akira Oka1, M.D., Ph.D., Kimi Araki7, Ph.D., Toru Furukawa4,8, M.D., Ph.D., Motoshi Hattori2, M.D., Ph.D. Affiliations 1Department of Pediatrics, The University of Tokyo, Tokyo, Japan 2Department of Pediatric Nephrology, Tokyo Women’s Medical University, Tokyo, Japan 3Department of Genetics, Hyogo College of Medicine, Hyogo, Japan 4Tokyo Women's Medical University Institute for Integrated Medical Sciences (TIIMS), Tokyo, Japan 1 5Department of Pathology, Kidney Center, Tokyo Women’s Medical University, School of Medicine, Tokyo, Japan 6Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan 7Division of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan 8Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan Correspondence to: Shoichiro Kanda, M.D., Ph.D. Assistant Professor Department of Pediatrics, The University of Tokyo, Tokyo, Japan 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan Tel.: +81-3-5800-8659 Fax: +81-3-3816-4108 E-mail: [email protected] 2 SUPPLEMENTAL MATERIAL TABLE OF CONTENTS Supplemental Table 1. Sequence performance data of the whole-exome sequence using SOLiD 5500 system. Supplemental Table 2. The coverage of the WES for 39 currently established monogenic causing genes for CAKUT. Supplemental Figure 1. Normalized coverage of the coding sequence around CBWD1. Supplemental Figure 2. The copy number profiles of the parents in the region containing a potential deletion in chromosome 9 from EXCAVATOR2. Supplemental Figure 3. Cbwd1 was not observed in E11.5 mouse kidneys. Supplemental Figure 4. CBWD1 was not observed in an adult human kidney. Supplemental Table 3. Genotype analysis of 4-week-old mice (C57BL/6N-Cbwd1em1). Supplemental Figure 5. DNA sequencing of the Cbwd1 locus from Cbwd1-deficient mice (C57BL/6N-Cbwd1em1). Supplemental Figure 6. DNA sequencing of the Cbwd1 locus from the Cbwd1 mutant (C57BL/6N-Cbwd1em2). Supplemental Table 4. Genotype analysis of 4-week-old mice (C57BL/6N-Cbwd1em2). Supplemental Figure 7. Percentages of newborn mice with CAKUT (C57BL/6N- Cbwd1em2). Supplemental Figure 8. CAKUT in Cbwd1 mutant mice (C57BL/6N-Cbwd1em2). 3 Supplemental Table 1. Sequence performance data of the whole-exome sequence using SOLiD 5500 system. 4 Supplemental Table 2. The coverage of the WES for 39 currently established monogenic causing genes for CAKUT. 5 Supplemental Figure 1. Normalized coverage of the coding sequence around CBWD1. The normalized coverage of CBWD1 coding sequence of both patients (II.1 and II.2) was zero. Meanwhile, the coverage of the younger healthy brother (II.3) was 0.39, and that of the parents (I.1 and I.2) was 0.27 (69%) and 0.23 (59%), being within the range that fitted heterozygosity. 6 Supplemental Figure 2. The copy number profiles of the parents in the region containing a potential deletion in chromosome 9 from EXCAVATOR2. Copy number segments (orange lines) were calculated from log2 plots of sequencing depth (blue dots) by applying the heterogeneous shifting level model (HSLM) algorithm. One copy number deletion in the particular region of CBWD1 was observed in the parents’ genome compared with that in the healthy sibling. 7 Supplemental Figure 3. Cbwd1 was not observed in E11.5 mouse kidneys. Four serial tissue sections of embryonic mouse kidneys (E11.5) were examined by hematoxylin and eosin staining and immunoperoxidase labeling for CBWD1, SIX2, and Cytokeratin 8. SIX2 is a marker of metanephric mesenchyme and Cytokeratin 8 (CK8) is a marker of ureteric bud. 8 Supplemental Figure 4. CBWD1 was not observed in an adult human kidney. A paraffin section of an adult human kidney was examined by immunoperoxidase labeling for CBWD1. 9 Supplemental Table 3. Genotype analysis of 4-week-old mice (C57BL/6N-Cbwd1em1). Cbwd1+/- mice were interbred. A total of 106 mice were genotyped at 4 weeks. Genotype Wild type Cbwd1 +/- Cbwd1 -/- Cases (n=106) 26 (25%) 59 (56%) 21 (20%) 10 Supplemental Figure 5. DNA sequencing of the Cbwd1 locus from Cbwd1-deficient mice (C57BL/6N-Cbwd1em1). Diagram of the Cbwd1 gene in the 5′–3′ direction displaying the gRNA genomic target regions and their respective PAM sequences. The wild-type sequence is shown at the top with the target site highlighted in blue and the PAM sequence in red. Strikethroughs indicate deletions. The Cbwd1-/- sequence is shown at the bottom and letters in purple indicate insertions. 11 Supplemental Figure 6. DNA sequencing of the Cbwd1 locus from the Cbwd1 mutant (C57BL/6N-Cbwd1em2). Diagram of the Cbwd1 gene in the 5′–3′ direction displaying the gRNA genomic target regions and their respective PAM sequences. The wild-type sequence is shown at the top with the target site highlighted in blue and the PAM sequence in red. Strikethroughs indicate deletions. The Cbwd1-/- sequence is shown at the bottom. 12 Supplemental Table 4. Genotype analysis of 4-week-old mice (C57BL/6N-Cbwd1em2). A second line of Cbwd1+/- mice was interbred. Fifty-one mice were genotyped at 4 weeks. Genotype Wild type Cbwd1 +/- Cbwd1 -/- Cases (n=51) 9 (18%) 31 (61%) 11 (22%) 13 Supplemental Figure 7. Percentages of newborn mice with CAKUT (C57BL/6N- Cbwd1em2). We examined the morphology of a second line of Cbwd1-/- mice. Three of five Cbwd1-/- mice and two of 20 Cbwd1+/- mice had identifiable CAKUT, while no abnormal phenotype was found in 13 wild-type (WT) mice. 14 Supplemental Figure 8. CAKUT in Cbwd1 mutant mice (C57BL/6N-Cbwd1em2). (A-C) Hematoxylin and eosin stained sections of kidneys from newborn mice at P0 [A, wild-type (WT); B, Cbwd1+/-; C, Cbwd1-/-]. Cbwd1+/- and Cbwd1-/- pups show hydronephrosis and hydroureter. (D and E) Higher magnification images of Panels A and C, respectively. Construction of renal tubules is disrupted and hyperplasia of the renal interstitium is observed in a kidney from a Cbwd1-/- pup. (F) Duplicated ureter from a 4- week-old Cbwd1+/- mouse. 15 .
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