| Autor: |
Yui Bong Alexander Wan, Yukiko Isekame, Jose Antonio Aragon-Martin, Daniel P. S. Osborn, Louise Benarroch, Maria Teresa Tome Esteban, Jaipreet Bharj, Guilleame Jondeau, Marjan Jahangiri, Anand Saggar, James Sneddon, Dongchuan Guo, Catherine Boileau, Elizabeth M. C. Fisher, Ellen S. Regalado, Alberto Smith, John Dean, Anne H. Child, Michael A. Simpson, Elijah R. Behr, Dianna M. Milewicz |
| Rok vydání: |
2017 |
| Předmět: |
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| DOI: |
10.1101/153452 |
| Popis: |
We describe a mutation inLMOD1, which predisposes individuals to thoracic aortic aneurysms and dissections in a large multi-generation British family. Exome variant profiles for the proband and two distantly related affected relatives were generated and a rare protein-altering, heterozygous variant was identified, present in all the exome-sequenced affected individuals. The allele c.1784T>C, p.(V595A) inLMOD1is located in a known actin-binding WH2 domain and is carried by all living affected individuals in the family.LMOD1was further assessed in a consecutive series of 98 UK TAAD patients and one further mutation was found, yielding an incidence of ∼2% in our study group. Assessment ofLMOD1in international TAAD cohorts discovered nine other missense variants of which three were classed as likely pathogenic.Validation ofLMOD1was undertaken using a zebrafish animal model. Knock-down of bothlmod1aandlmod1bparalogs using morpholino oligonucleotides showed a reproducible abnormal phenotype involving the aortic arches under off-target controls. Injection of the humanLMOD1c.1784T>C, p.(V595A) mutation demonstrated a likely dominant negative effect and illustrated a loss of function cause.Mutations found in the WH2 actin-binding domain ofLMOD1may delay actin polymerization and therefore compromise actin length, dynamics and interaction with myosin in the smooth muscle contraction pathway. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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