|Title||LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Guo, D-C, Regalado, ES, Gong, L, Duan, X, Santos-Cortez, RLyn P, Arnaud, P, Ren, Z, Cai, B, Hostetler, EM, Moran, R, Liang, D, Estrera, A, Safi, HJ, Leal, SM, Bamshad, MJ, Shendure, J, Nickerson, DA, Jondeau, G, Boileau, C, Milewicz, DM|
|Corporate Authors||University of Washington Center for Mendelian Genomics|
|Date Published||2016 Mar 18|
|Keywords||Adult, Aged, Amino Acid Sequence, Aneurysm, Dissecting, Aortic Aneurysm, Thoracic, Female, Genetic Variation, Humans, Male, Middle Aged, Molecular Sequence Data, Mutation, Pedigree, Protein-Lysine 6-Oxidase|
RATIONALE: Mutations in several genes have been identified that are responsible for 25% of families with familial thoracic aortic aneurysms and dissections. However, the causative gene remains unknown in 75% of families.
OBJECTIVES: To identify the causative mutation in families with autosomal dominant inheritance of thoracic aortic aneurysms and dissections.
METHODS AND RESULTS: Exome sequencing was used to identify the mutation responsible for a large family with thoracic aortic aneurysms and dissections. A heterozygous rare variant, c.839G>T (p.Ser280Arg), was identified in LOX, encoding a lysyl oxidase, that segregated with disease in the family. Sanger and exome sequencing was used to investigate mutations in LOX in an additional 410 probands from unrelated families. Additional LOX rare variants that segregated with disease in families were identified, including c.125G>A (p.Trp42*), c.604G>T (p.Gly202*), c.743C>T (p.Thr248Ile), c.800A>C (p.Gln267Pro), and c.1044T>A (p.Ser348Arg). The altered amino acids cause haploinsufficiency for LOX or are located at a highly conserved LOX catalytic domain, which is relatively invariant in the population. Expression of the LOX variants p.Ser280Arg and p.Ser348Arg resulted in significantly lower lysyl oxidase activity when compared with the wild-type protein. Individuals with LOX variants had fusiform enlargement of the root and ascending thoracic aorta, leading to ascending aortic dissections.
CONCLUSIONS: These data, along with previous studies showing that the deficiency of LOX in mice or inhibition of lysyl oxidases in turkeys and rats causes aortic dissections, support the conclusion that rare genetic variants in LOX predispose to thoracic aortic disease.
|Alternate Journal||Circ. Res.|
|PubMed Central ID||PMC4839295|
|Grant List||U54 HG006493 / HG / NHGRI NIH HHS / United States |
R01 HL062594 / HL / NHLBI NIH HHS / United States
UL1 RR024148 / RR / NCRR NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
R01 HL62594 / HL / NHLBI NIH HHS / United States
1U54HG006493 / HG / NHGRI NIH HHS / United States
P01HL110869-01 / HL / NHLBI NIH HHS / United States
P01 HL110869 / HL / NHLBI NIH HHS / United States
R01 HL109942 / HL / NHLBI NIH HHS / United States