Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita
| Autor: | Loic Quevarec, Florent Marguet, Bruno Reversade, Martine Bucourt, Ivo Gut, Mohammad Shboul, Jérome Maluenda, Alvin Yu Jin Ng, Shifeng Xue, Jacinda B. Sampson, Luc Rigonnot, Annie Laquerrière, Sandra Whalen, Carolina Tesi Rocha, Thong Teck Tan, Sumanty Tohari, Fawaz Alkazaleh, Carine Bonnard, Byrappa Venkatesh, Kristin G. Monaghan, Marta Gut, Marie Gonzales, Carly E. Siskind, Mung Kei Kong, Judith Melki, Megan T. Cho |
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| Přispěvatelé: | Center for Reproductive Medicine, Amsterdam Reproduction & Development (AR&D), ACS - Heart failure & arrhythmias, ACS - Diabetes & metabolism |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male ADAM22 Schwann cell Nerve Tissue Proteins 030105 genetics & heredity Biology 03 medical and health sciences Myelin Immunolabeling Germline mutation Report Genetics medicine Humans Genetics (clinical) Loss function Myelin Sheath Arthrogryposis Arthrogryposis multiplex congenital Extracellular Matrix Proteins Arthrogryposis multiplex congenita Peripheral hypomyelination Infant Newborn Secreted ligand Infant Molecular biology Pedigree 030104 developmental biology medicine.anatomical_structure Whole-exome sequencing Child Preschool Mutation Female LGI4 Schwann Cells medicine.symptom Hypomyelination |
| Zdroj: | American journal of human genetics, 100(4), 659-665. Cell Press |
| ISSN: | 0002-9297 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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