PT  - JOURNAL ARTICLE
AU  - Y.B.A. Wan
AU  - M.A. Simpson
AU  - J.A. Aragon-Martin
AU  - D.P.S. Osborn
AU  - E. Regalado
AU  - D.C. Guo
AU  - C. Boileau
AU  - G. Jondeau
AU  - L. Benarroch
AU  - Y. Isekame
AU  - J. Bharj
AU  - J. Sneddon
AU  - E. Fisher
AU  - J. Dean
AU  - M.T. Tome Esteban
AU  - A. Saggar
AU  - D. Milewicz
AU  - M. Jahangiri
AU  - E. R. Behr
AU  - A. Smith
AU  - A. H. Child
TI  - A mutation in the <em>LMOD1</em> actin-binding domain segregating with disease in a large British family with thoracic aortic aneurysms and dissections
AID  - 10.1101/153452
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 153452
4099  - http://biorxiv.org/content/early/2017/07/14/153452.short
4100  - http://biorxiv.org/content/early/2017/07/14/153452.full
AB  - We describe a mutation in LMOD1, 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) in LMOD1 is located in a known actin-binding WH2 domain and is carried by all living affected individuals in the family. LMOD1 was 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 of LMOD1 in international TAAD cohorts discovered nine other missense variants of which three were classed as likely pathogenic.Validation of LMOD1 was undertaken using a zebrafish animal model. Knock-down of both lmod1a and lmod1b paralogs using morpholino oligonucleotides showed a reproducible abnormal phenotype involving the aortic arches under off-target controls. Injection of the human LMOD1 c.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 of LMOD1 may delay actin polymerization and therefore compromise actin length, dynamics and interaction with myosin in the smooth muscle contraction pathway.