2. Academic Validation
  3. Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita

Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita

  • Am J Hum Genet. 2017 Apr 6;100(4):659-665. doi: 10.1016/j.ajhg.2017.02.006.
Shifeng Xue 1,  Jérôme Maluenda 2,  Florent Marguet 3,  Mohammad Shboul 4,  Loïc Quevarec 2,  Carine Bonnard 4,  Alvin Yu Jin Ng 5,  Sumanty Tohari 5,  Thong Teck Tan 4,  Mung Kei Kong 4,  Kristin G Monaghan 6,  Megan T Cho 6,  Carly E Siskind 7,  Jacinda B Sampson 7,  Carolina Tesi Rocha 7,  Fawaz Alkazaleh 8,  Marie Gonzales 9,  Luc Rigonnot 10,  Sandra Whalen 9,  Marta Gut 11,  Ivo Gut 11,  Martine Bucourt 12,  Byrappa Venkatesh 13,  Annie Laquerrière 3,  Bruno Reversade 14,  Judith Melki 15
Affiliations

Affiliations

  • 1 Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore.
  • 2 Institut National de la Santé et de la Recherche Médicale (Inserm) UMR-1169, Université Paris Sud, Le Kremlin Bicêtre 94276, France.
  • 3 Pathology Laboratory, Rouen University Hospital, Rouen 76000, France; Normandie Univ, UNIROUEN, INSERM, CHU Rouen, Laboratoire NeoVasc ERI28, Rouen 76000, France.
  • 4 Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore.
  • 5 Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore.
  • 6 GeneDx, Gaithersburg, MD 20877, USA.
  • 7 Stanford University, Stanford, CA 94304, USA.
  • 8 Department of Obstetrics and Gynecology, University of Jordan, Amman 19241, Jordan.
  • 9 Département de Génétique Médicale, Hôpital Trousseau, Université Pierre et Marie Curie, Paris 75571, France.
  • 10 Service d'Obstétrique, Centre Hospitalier Sud-Francilien, Corbeil-Essonnes 91100, France.
  • 11 CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain; Universitat Pompeu Fabra (UPF), Barcelona 08028, Spain.
  • 12 Unité de fœtopathologie, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Hôpital Jean Verdier, Bondy 93143, France.
  • 13 Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore; Department of Paediatrics, School of Medicine, National University of Singapore, Singapore 119228, Singapore.
  • 14 Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore; Department of Medical Genetics, Koç University, School of Medicine (KUSoM), Istanbul 34450, Turkey; Department of Paediatrics, School of Medicine, National University of Singapore, Singapore 119228, Singapore; Amsterdam Reproduction & Development, Academic Medical Centre & VU University Medical Center, Amsterdam 1105 AZ, the Netherlands. Electronic address: bruno@reversade.com.
  • 15 Institut National de la Santé et de la Recherche Médicale (Inserm) UMR-1169, Université Paris Sud, Le Kremlin Bicêtre 94276, France. Electronic address: judith.melki@inserm.fr.
PMID: 28318499 DOI: 10.1016/j.ajhg.2017.02.006
Abstract

Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome Sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.

Keywords

ADAM22; LGI4; Schwann cells; arthrogryposis multiplex congenital; hypomyelination; secreted ligand; whole-exome sequencing.

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