Functional Loss of Semaphorin 3C and/or Semaphorin 3D and Their Epistatic Interaction with Ret Are Critical to Hirschsprung Disease Liability
| Autor: | Raquel M. Fernández, Seneca L. Bessling, Grzegorz M. Burzynski, Albee Y. Ling, Salud Borrego, Isabella Ceccherini, Andrew S. McCallion, Aravinda Chakravarti, Moltu Guy, Robert M.W. Hofstra, Qian Jiang, Stacey Arnold, Jeffrey J. Gray, Jeanne Amiel, Krishna Praneeth Kilambi, Maria X. Sosa, Vassilis Pachnis, Betty Q. Doan, Ashish Kapoor, Stanislas Lyonnet, Qingguang Jiang, Tiffany A. Heanue, Kristen West, Joke B. G. M. Verheij, Paola Griseri |
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| Přispěvatelé: | Clinical Genetics |
| Rok vydání: | 2015 |
| Předmět: |
EXPRESSION
MIGRATION Cellular differentiation Molecular Sequence Data TYROSINE KINASE Genome-wide association study Semaphorins Article ENHANCER Mice ENTERIC NERVOUS-SYSTEM Semaphorin Genetics Neuropilin Animals Genetics(clinical) Genetic Predisposition to Disease Hirschsprung Disease CELL GENOME-WIDE ASSOCIATION COMMON Genetics (clinical) Loss function Base Sequence RECEPTOR biology Proto-Oncogene Proteins c-ret Plexin Genetic Variation Epistasis Genetic SEMA3A Sequence Analysis DNA MARKER biology.protein Genome-Wide Association Study |
| Zdroj: | American Journal of Human Genetics, 96(4), 581-596. Cell Press American Journal of Human Genetics, 96(4), 581-596. CELL PRESS |
| ISSN: | 0002-9297 |
| Popis: | Innervation of the gut is segmentally lost in Hirschsprung disease (HSCR), a consequence of cell-autonomous and non-autonomous defects in enteric neuronal cell differentiation, proliferation, migration, or survival. Rare, high-penetrance coding variants and common, low-penetrance non-coding variants in 13 genes are known to underlie HSCR risk, with the most frequent variants in the ret proto-oncogene (RET). We used a genome-wide association (220 trios) and replication (429 trios) study to reveal a second non-coding variant distal to RET and a non-coding allele on chromosome 7 within the class 3 Semaphorin gene cluster. Analysis in Ret wild-type and Ret-null mice demonstrates specific expression of Sema3a, Sema3c, and Sema3d in the enteric nervous system (ENS). In zebrafish embryos, sema3 knockdowns show reduction of migratory ENS precursors with complete ablation under conjoint ret loss of function. Seven candidate receptors of Sema3 proteins are also expressed within the mouse ENS and their expression is also lost in the ENS of Ret-null embryos. Sequencing of SEMA3A, SEMA3C, and SEMA3D in 254 HSCR-affected subjects followed by in silico protein structure modeling and functional analyses identified five disease-associated alleles with loss-of-function defects in semaphorin dimerization and binding to their cognate neuropilin and plexin receptors. Thus, semaphorin 3C/3D signaling is an evolutionarily conserved regulator of ENS development whose dys-regulation is a cause of enteric aganglionosis. |
| Databáze: | OpenAIRE |
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