A Multiplex Kindred with Hennekam Syndrome due to Homozygosity for a CCBE1 Mutation that does not Prevent Protein Expression

详细信息    查看全文

• 作者：Carolyn C. Jackson ; Lucy Best ; Lazaro Lorenzo…
• 关键词：Hennekam Syndrome ; lymphedema ; lymphangiectasia ; CCBE1
• 刊名：Journal of Clinical Immunology
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：36
• 期：1
• 页码：19-27
• 全文大小：1,889 KB
• 参考文献：1.Hennekam RC, Geerdink RA, Hamel BC, Hennekam FA, Kraus P, Rammeloo JA, et al. Autosomal recessive intestinal lymphangiectasia and lymphedema, with facial anomalies and mental retardation. Am J Med Genet. 1989;34(4):593–600.PubMed CrossRef
  2.Al-Gazali LI, Hertecant J, Ahmed R, Khan NA, Padmanabhan R. Further delineation of Hennekam syndrome. Clin Dysmorphol. 2003;12(4):227–32.PubMed CrossRef
  3.Bellini C, Mazzella M, Arioni C, Campisi C, Taddei G, Toma P, et al. Hennekam syndrome presenting as nonimmune hydrops fetalis, congenital chylothorax, and congenital pulmonary lymphangiectasia. Am J Med Genet A. 2003;120A(1):92–6.PubMed CrossRef
  4.Connell F, Kalidas K, Ostergaard P, Brice G, Homfray T, Roberts L, et al. Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia. Hum Genet. 2010;127(2):231–41.PubMed CrossRef
  5.Cormier-Daire V, Lyonnet S, Lehnert A, Martin D, Salomon R, Patey N, et al. Craniosynostosis and kidney malformation in a case of Hennekam syndrome. Am J Med Genet. 1995;57(1):66–8.PubMed CrossRef
  6.Forzano F, Faravelli F, Loy A, Di Rocco M. Severe lymphedema, intestinal lymphangiectasia, seizures and mild mental retardation: further case of Hennekam syndrome with a severe phenotype. Am J Med Genet. 2002;111(1):68–70.PubMed CrossRef
  7.Gabrielli O, Catassi C, Carlucci A, Coppa GV, Giorgi P. Intestinal lymphangiectasia, lymphedema, mental retardation, and typical face: confirmation of the Hennekam syndrome. Am J Med Genet. 1991;40(2):244–7.PubMed CrossRef
  8.Scarcella A, De Lucia A, Pasquariello MB, Gambardella P. Early death in two sisters with Hennekam syndrome. Am J Med Genet. 2000;93(3):181–3.PubMed CrossRef
  9.Van Balkom ID, Alders M, Allanson J, Bellini C, Frank U, De Jong G, et al. Lymphedema-lymphangiectasia-mental retardation (Hennekam) syndrome: a review. Am J Med Genet. 2002;112(4):412–21.PubMed CrossRef
  10.Yasunaga M, Yamanaka C, Mayumi M, Momoi T, Mikawa H. Protein-losing gastroenteropathy with facial anomaly and growth retardation: a mild case of Hennekam syndrome. Am J Med Genet. 1993;45(4):477–80.PubMed CrossRef
  11.Alders M, Hogan BM, Gjini E, Salehi F, Al-Gazali L, Hennekam EA, et al. Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nat Genet. 2009;41(12):1272–4.PubMed CrossRef
  12.Alders M, Mendola A, Ades L, Al Gazali L, Bellini C, Dallapiccola B, et al. Evaluation of clinical manifestations in patients with severe lymphedema with and without CCBE1 mutations. Mol Syndromol. 2013;4(3):107–13.PubMed PubMedCentral
  13.Alders M, Al-Gazali L, Cordeiro I, Dallapiccola B, Garavelli L, Tuysuz B, et al. Hennekam syndrome can be caused by FAT4 mutations and be allelic to Van Maldergem syndrome. Hum Genet. 2014;133(9):1161–7.PubMed CrossRef
  14.Bos FL, Caunt M, Peterson-Maduro J, Planas-Paz L, Kowalski J, Karpanen T, et al. CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circ Res. 2011;109(5):486–91.PubMed CrossRef
  15.Jeltsch M, Jha SK, Tvorogov D, Anisimov A, Leppanen VM, Holopainen T, et al. CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation. Circulation. 2014;129(19):1962–71.PubMed CrossRef
  16.Hogan BM, Bos FL, Bussmann J, Witte M, Chi NC, Duckers HJ, et al. Ccbe1 is required for embryonic lymphangiogenesis and venous sprouting. Nat Genet. 2009;41(4):396–8.PubMed CrossRef
  17.Shah S, Conlin LK, Gomez L, Aagenaes O, Eiklid K, Knisely AS, et al. CCBE1 mutation in two siblings, one manifesting lymphedema-cholestasis syndrome, and the other, fetal hydrops. PLoS One. 2013;8(9):e75770.PubMed PubMedCentral CrossRef
  18.Mendola A, Schlogel MJ, Ghalamkarpour A, Irrthum A, Nguyen HL, Fastre E, et al. Mutations in the VEGFR3 signaling pathway explain 36% of familial lymphedema. Mol Syndromol. 2013;4(6):257–66.PubMed PubMedCentral CrossRef
  19.Le Guen L, Karpanen T, Schulte D, Harris NC, Koltowska K, Roukens G, et al. Ccbe1 regulates Vegfc-mediated induction of Vegfr3 signaling during embryonic lymphangiogenesis. Development. 2014;141(6):1239–49.PubMed CrossRef
  20.Weijts BG, van Impel A, Schulte-Merker S, de Bruin A. Atypical E2fs control lymphangiogenesis through transcriptional regulation of Ccbe1 and Flt4. PLoS One. 2013;8(9):e73693.PubMed PubMedCentral CrossRef
  21.Ingle SB, Hinge Ingle CR. Primary intestinal lymphangiectasia: minireview. World J Clin Cases. 2014;2(10):528–33.PubMed PubMedCentral CrossRef
  22.Vignes S, Bellanger J. Primary intestinal lymphangiectasia (Waldmann’s disease). Orphanet J Rare Dis. 2008;3:5.PubMed PubMedCentral CrossRef
  23.Bolze A, Byun M, McDonald D, Morgan NV, Abhyankar A, Premkumar L, et al. Whole-exome-sequencing-based discovery of human FADD deficiency. Am J Hum Genet. 2010;87(6):873–81.PubMed PubMedCentral CrossRef
  24.Byun M, Abhyankar A, Lelarge V, Plancoulaine S, Palanduz A, Telhan L, et al. Whole-exome sequencing-based discovery of STIM1 deficiency in a child with fatal classic Kaposi sarcoma. J Exp Med. 2010;207(11):2307–12.PubMed PubMedCentral CrossRef
  25.UniProt C. UniProt: a hub for protein information. Nucleic Acids Res. 2015;43(Database issue):D204–12.
  26.Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7(4):248–9.PubMed PubMedCentral CrossRef
  27.Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46(3):310–5.PubMed PubMedCentral CrossRef
  28.Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc. 2009;4(7):1073–81.PubMed CrossRef
  29.Itan Y, Shang L, Boisson B, Patin E, Bolze A, Moncada-Velez M, et al. The human gene damage index as a gene-level approach to prioritizing exome variants. Proc Natl Acad Sci USA. 2015;112(44):13615–20.
  30.Conley ME, Casanova JL. Discovery of single-gene inborn errors of immunity by next generation sequencing. Curr Opin Immunol. 2014;30:17–23.PubMed CrossRef
  31.Casanova JL, Conley ME, Seligman SJ, Abel L, Notarangelo LD. Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies. J Exp Med. 2014;211(11):2137–49.PubMed PubMedCentral CrossRef
  32.Roukens MG, Peterson-Maduro J, Padberg Y, Jeltsch M, Leppanen VM, Bos FL, et al. Functional dissection of the CCBE1 protein: a crucial requirement for the collagen repeat domain. Circ Res. 2015;116(10):1660–9.PubMed CrossRef
  33.Connell FC, Kalidas K, Ostergaard P, Brice G, Murday V, Mortimer PS, et al. CCBE1 mutations can cause a mild, atypical form of generalized lymphatic dysplasia but are not a common cause of non-immune hydrops fetalis. Clin Genet. 2012;81(2):191–7.PubMed CrossRef
  
• 作者单位：Carolyn C. Jackson (1) (2)
  Lucy Best (1)
  Lazaro Lorenzo (3)
  Jean-Laurent Casanova (1) (3) (4) (5) (6)
  Jochen Wacker (7)
  Simone Bertz (7)
  Abbas Agaimy (7)
  Thomas Harrer (8)
  
  1. St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY, USA
  2. Department of Pediatrics, The Memorial Sloan Kettering Cancer Center, New York, NY, USA
  3. Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, INSERM, Paris, France
  4. Howard Hughes Medical Institute, New York, NY, USA
  5. Paris Descartes University, Imagine Institute, Paris, France
  6. Pediatric Hematology-Immunology Unit, Necker Hospital for Sick Children, Paris, France
  7. Department of Pathology, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
  8. Department for Internal Medicine III, Universitätsklinikum Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany
  
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biomedicine
  Immunology
  Infectious Diseases
  Internal Medicine
  Medical Microbiology
  
• 出版者：Springer Netherlands
• ISSN：1573-2592

文摘

Collagen and calcium-binding EGF domain-containing protein 1 (CCBE1) bi-allelic mutations have been associated with syndromes of widespread congenital lymphatic dysplasia, including Hennekam Syndrome (HS). HS is characterized by lymphedema, lymphangiectasia, and intellectual disability. CCBE1 encodes a putative extracellular matrix protein but the HS-causing mutations have not been studied biochemically. We report two HS siblings, born to consanguineous parents of Turkish ancestry, whose clinical phenotype also includes protein losing enteropathy, painful relapsing chylous ascites, and hypogammaglobulinemia. We identified by whole exome and Sanger sequencing the homozygous CCBE1 C174Y mutation in both siblings. This mutation had been previously reported in another HS kindred from the Netherlands. In over-expression studies, we found increased intracellular expression of all forms (monomers, dimers, trimers) of the CCBE1 C174Y mutant protein, by Western blot, despite mutant mRNA levels similar to wild-type (WT). In addition, we detected increased secretion of the mutant CCBE1 protein by ELISA. We further found the mutant and WT proteins to be evenly distributed in the cytoplasm, by immunofluorescence and confocal microscopy. Finally, we found a strong decrease of lymphatic vessels, with a corresponding diminished expression of CCBE1, by immunohistochemistry of the patients’ intestinal biopsies. In contrast, mucosal blood vessels and muscularis mucosae showed normal CCBE1 staining. Our findings show that the mutant CCBE1 C174Y protein is not loss-of-function by loss-of-expression. Keywords Hennekam Syndrome lymphedema lymphangiectasia CCBE1