RT Journal Article SR Electronic T1 A mutation in the LMOD1 actin-binding domain segregating with disease in a large British family with thoracic aortic aneurysms and dissections JF bioRxiv FD Cold Spring Harbor Laboratory SP 153452 DO 10.1101/153452 A1 Y.B.A. Wan A1 M.A. Simpson A1 J.A. Aragon-Martin A1 D.P.S. Osborn A1 E. Regalado A1 D.C. Guo A1 C. Boileau A1 G. Jondeau A1 L. Benarroch A1 Y. Isekame A1 J. Bharj A1 J. Sneddon A1 E. Fisher A1 J. Dean A1 M.T. Tome Esteban A1 A. Saggar A1 D. Milewicz A1 M. Jahangiri A1 E. R. Behr A1 A. Smith A1 A. H. Child YR 2017 UL http://biorxiv.org/content/early/2017/07/14/153452.abstract 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.