Two Months, Two Genes

The John Ritter Research Program got off to a great start this year. Two months into 2016, the group has already published new research identifying two new genes  for aortic disease. Your contributions to support the research program are instrumental in making this rapid pace of research possible. A brief description of these papers follows.

1. FOXE3 mutations predispose to thoracic aortic aneurysms and dissections.

Published in: The Journal of  Clinical Investigation. 2016 Feb 8. pii: 83778. doi: 10.1172/JCI83778. [Epub ahead of print]

Kuang SQ, Medina-Martinez O, Guo DC, Gong L, Regalado ES, Reynolds CL, Boileau C, Jondeau G, Prakash SK, Kwartler CS, Zhu LY, Peters AM, Duan XY, Bamshad MJ, Shendure J, Nickerson DA, Santos-Cortez RL, Dong X, Leal SM, Majesky MW, Swindell EC, Jamrich M, Milewicz DM.

The ascending thoracic aorta is designed to withstand biomechanical forces from pulsatile blood. Thoracic aortic aneurysms and acute aortic dissections (TAADs) occur as a result of genetically triggered defects in aortic structure and a dysfunctional response to these forces. Here, we describe mutations in the forkhead transcription factor FOXE3 that predispose mutation-bearing individuals to TAAD. We performed exome sequencing of a large family with multiple members with TAADs and identified a rare variant in FOXE3 with an altered amino acid in the DNA-binding domain (p.Asp153His) that segregated with disease in this family. Additional pathogenic FOXE3 variants were identified in unrelated TAAD families. In mice, Foxe3 deficiency reduced smooth muscle cell (SMC) density and impaired SMC differentiation in the ascending aorta. Foxe3 expression was induced in aortic SMCs after transverse aortic constriction, and Foxe3 deficiency increased SMC apoptosis and ascending aortic rupture with increased aortic pressure. These phenotypes were rescued by inhibiting p53 activity, either by administration of a p53 inhibitor (pifithrin-α), or by crossing Foxe3-/- mice with p53-/- mice. Our data demonstrate that FOXE3 mutations lead to a reduced number of aortic SMCs during development and increased SMC apoptosis in the ascending aorta in response to increased biomechanical forces, thus defining an additional molecular pathway that leads to familial thoracic aortic disease.

2. LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections.

Published in: Circulation Research. 2016 Jan 12. pii: CIRCRESAHA.115.307130. [Epub ahead of print]

Guo D, Regalado ES, Gong L, Duan X, Santos-Cortez RL, Arnaud P, Ren Z, Cai B, Hostetler EM, Moran R, Liang D, Estrera AL, Safi HJ, Leal SM, Bamshad MJ, Shendure J, Nickerson DA, Jondeau G, Boileau C, Milewicz DM.

RATIONALE: Mutations in several genes have been identified that are responsible for approximately 25% of families with familial thoracic aortic aneurysms and dissections (TAAD). However, the causative gene remains unknown in 75% of families.

OBJECTIVE: To identify the causative mutation in families with autosomal dominant inheritance of TAAD.

METHODS AND RESULTS: Exome sequencing was used to identify the mutation responsible for a large family with TAAD. 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 performed to investigate mutations in candidate genes 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 had 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 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.

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