A mutation in the LMOD1 actin-binding domain segregating with disease in a large British family with thoracic aortic aneurysms and dissections

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.