Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita.
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.
Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore.
Shifeng
S
Xue
Institut National de la Santé et de la Recherche Médicale (Inserm) UMR-1169, Université Paris Sud, Le Kremlin Bicêtre 94276, France.
Jérôme
J
Maluenda
Pathology Laboratory, Rouen University Hospital, Rouen 76000, France; Normandie Univ, UNIROUEN, INSERM, CHU Rouen, Laboratoire NeoVasc ERI28, Rouen 76000, France.
Florent
F
Marguet
Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore.
Mohammad
M
Shboul
Institut National de la Santé et de la Recherche Médicale (Inserm) UMR-1169, Université Paris Sud, Le Kremlin Bicêtre 94276, France.
Loïc
L
Quevarec
Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore.
Carine
C
Bonnard
Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore.
Alvin Yu Jin
AY
Ng
Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore.
Sumanty
S
Tohari
Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore.
Thong Teck
TT
Tan
Institute of Medical Biology, A(∗)STAR, Singapore 138648, Singapore.
Mung Kei
MK
Kong
GeneDx, Gaithersburg, MD 20877, USA.
Kristin G
KG
Monaghan
GeneDx, Gaithersburg, MD 20877, USA.
Megan T
MT
Cho
Stanford University, Stanford, CA 94304, USA.
Carly E
CE
Siskind
Stanford University, Stanford, CA 94304, USA.
Jacinda B
JB
Sampson
Stanford University, Stanford, CA 94304, USA.
Carolina Tesi
CT
Rocha
Department of Obstetrics and Gynecology, University of Jordan, Amman 19241, Jordan.
Fawaz
F
Alkazaleh
Département de Génétique Médicale, Hôpital Trousseau, Université Pierre et Marie Curie, Paris 75571, France.
Marie
M
Gonzales
Service d'Obstétrique, Centre Hospitalier Sud-Francilien, Corbeil-Essonnes 91100, France.
Luc
L
Rigonnot
Département de Génétique Médicale, Hôpital Trousseau, Université Pierre et Marie Curie, Paris 75571, France.
Sandra
S
Whalen
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain; Universitat Pompeu Fabra (UPF), Barcelona 08028, Spain.
Marta
M
Gut
CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona 08028, Spain; Universitat Pompeu Fabra (UPF), Barcelona 08028, Spain.
Ivo
I
Gut
Unité de fœtopathologie, Hôpitaux Universitaires Paris-Seine-Saint-Denis, Hôpital Jean Verdier, Bondy 93143, France.
Martine
M
Bucourt
Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore; Department of Paediatrics, School of Medicine, National University of Singapore, Singapore 119228, Singapore.
Byrappa
B
Venkatesh
Pathology Laboratory, Rouen University Hospital, Rouen 76000, France; Normandie Univ, UNIROUEN, INSERM, CHU Rouen, Laboratoire NeoVasc ERI28, Rouen 76000, France.
Annie
A
Laquerrière
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.
Bruno
B
Reversade
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.
Judith
J
Melki
D001176:Arthrogryposis / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D002675:Child, Preschool; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D009186:Myelin Sheath / Q000378:metabolism; D009419:Nerve Tissue Proteins; D010375:Pedigree; D012583:Schwann Cells / Q000378:metabolism*
D016326:Extracellular Matrix Proteins; C488167:LGI4 protein, human; D009419:Nerve Tissue Proteins
ADAM22; LGI4; Schwann cells; arthrogryposis multiplex congenital; hypomyelination; secreted ligand; whole-exome sequencing