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LOX Mutations Predispose to Thoracic Aortic Aneurysms and Dissections

Published on Mar 18, 2016in Circulation Research15.86
· DOI :10.1161/CIRCRESAHA.115.307130
Dongchuan Guo33
Estimated H-index: 33
(University of Texas Health Science Center at Houston),
Ellen S. Regalado25
Estimated H-index: 25
(University of Texas Health Science Center at Houston)
+ 17 AuthorsDianna M. Milewicz58
Estimated H-index: 58
(University of Texas Health Science Center at Houston)
Abstract
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. # Novelty and Significance {#article-title-29}
  • References (28)
  • Citations (54)
References28
Newest
#1Lixin Jia (Capital Medical University)H-Index: 21
#2Wen-Mei Zhang (Capital Medical University)H-Index: 6
Last.Jie Du (Capital Medical University)H-Index: 47
view all 8 authors...
#1Dongchuan Guo (University of Texas Health Science Center at Houston)H-Index: 33
#2Ellen S. Regalado (University of Texas Health Science Center at Houston)H-Index: 25
Last.Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 58
view all 20 authors...
#1Tomohiro Kurihara (Keio: Keio University)H-Index: 5
#2Ryoko Shimizu-Hirota (Keio: Keio University)H-Index: 14
Last.Yasunori Okada (Keio: Keio University)H-Index: 80
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#1Catherine BoileauH-Index: 63
#2Dongchuan Guo (University of Texas Health Science Center at Houston)H-Index: 33
Last.Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 58
view all 26 authors...
#1Ellen S. Regalado (University of Texas Health Science Center at Houston)H-Index: 25
#2Dongchuan Guo (University of Texas Health Science Center at Houston)H-Index: 33
Last.Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 58
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#1Li Wang (University of Texas Health Science Center at Houston)H-Index: 2
#2Dongchuan Guo (University of Texas Health Science Center at Houston)H-Index: 33
Last.Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 58
view all 15 authors...
Cited By54
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#1Valeriana Cesarini (Sapienza University of Rome)H-Index: 2
#2C Pisano (Sapienza University of Rome)H-Index: 1
Last.Susanna Dolci (Sapienza University of Rome)H-Index: 36
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#1Jing-Jing Luo (HAU: Huazhong Agricultural University)H-Index: 1
#2Yu Zhang (HAU: Huazhong Agricultural University)H-Index: 1
Last.Lv-Hui Sun (HAU: Huazhong Agricultural University)H-Index: 10
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#1Tamara Rosell-García (UAM: Autonomous University of Madrid)H-Index: 1
#2Alberto Paradela (CSIC: Spanish National Research Council)H-Index: 20
Last.Fernando Rodríguez-Pascual (UAM: Autonomous University of Madrid)H-Index: 21
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#1Xue-Yan Duan (University of Texas Health Science Center at Houston)H-Index: 1
#2Dongchuan Guo (University of Texas Health Science Center at Houston)H-Index: 33
Last.Dianna M. Milewicz (University of Texas Health Science Center at Houston)H-Index: 58
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#1Marion A. Hofmann Bowman (UM: University of Michigan)H-Index: 1
#2Kim A. Eagle (UM: University of Michigan)H-Index: 115
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#1Jennifer Thomson (MAHSC: Manchester Academic Health Science Centre)H-Index: 1
#2Mukti Singh (MAHSC: Manchester Academic Health Science Centre)H-Index: 3
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