دورية أكاديمية
LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections.
| العنوان: | LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections. |
|---|---|
| المؤلفون: | Guo DC; Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA., Regalado ES; Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA., Pinard A; Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA., Chen J; Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA., Lee K; Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Rigelsky C; Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA., Zilberberg L; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA., Hostetler EM; Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA., Aldred M; Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA., Wallace SE; Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA., Prakash SK; Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA., Leal SM; Department of Molecular and Human Genetics, Center for Statistical Genetics, Baylor College of Medicine, Houston, TX 77030, USA., Bamshad MJ; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Nickerson DA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA., Natowicz M; Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA., Rifkin DB; Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA., Milewicz DM; Department of Internal Medicine, University of Texas Health Science Center at Houston McGovern Medical School, Houston, TX 77030, USA. Electronic address: dianna.m.milewicz@uth.tmc.edu. |
| مؤلفون مشاركون: | University of Washington Center for Mendelian Genomics |
| المصدر: | American journal of human genetics [Am J Hum Genet] 2018 Apr 05; Vol. 102 (4), pp. 706-712. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2008- : [Cambridge, MA] : Cell Press Original Publication: Baltimore, American Society of Human Genetics. |
| مواضيع طبية MeSH: | Genetic Predisposition to Disease*, Aortic Dissection/*genetics , Aortic Aneurysm, Thoracic/*genetics , Latent TGF-beta Binding Proteins/*genetics , Mutation/*genetics, Adult ; Aged, 80 and over ; Animals ; Blood Pressure/genetics ; Female ; Homozygote ; Humans ; Male ; Mice ; Middle Aged ; Pedigree |
| مستخلص: | The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs ∗ 25 and p.Glu750 ∗ ) in LTBP3 were identified in affected members of one family. A homozygous variant (p.Asn678_Gly681delinsThrCys) that introduces an additional cysteine into an epidermal growth factor (EGF)-like domain in the corresponding protein, latent TGF-β binding protein (LTBP-3), was identified in a second family. Individuals with compound heterozygous or homozygous variants in these families have aneurysms and dissections of the thoracic aorta, as well as aneurysms of the abdominal aorta and other arteries, along with dental abnormalities and short stature. Heterozygous carriers of the p.Asn678_Gly681delinsThrCys variant have later onset of thoracic aortic disease, as well as dental abnormalities. In these families, LTBP3 variants segregated with thoracic aortic disease with a combined LOD score of 3.9. Additionally, heterozygous rare LTBP3 variants were found in individuals with early onset of acute aortic dissections, and some of these variants disrupted LTBP-3 levels or EGF-like domains. When compared to wild-type mice, Ltbp3 -/- mice have enlarged aortic roots and ascending aortas. In summary, homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities. (Copyright © 2018 American Society of Human Genetics. All rights reserved.) |
| References: | J Am Coll Cardiol. 2017 Nov 28;70(21):2728-2730. (PMID: 29169482) Nat Genet. 2006 Mar;38(3):343-9. (PMID: 16444274) J Am Coll Cardiol. 2010 Apr 6;55(14):e27-e129. (PMID: 20359588) Biochem J. 2011 Jan 15;433(2):263-76. (PMID: 21175431) Nat Genet. 2003 Mar;33(3):407-11. (PMID: 12598898) Am J Hum Genet. 2009 Apr;84(4):519-23. (PMID: 19344874) Nat Med. 2007 Feb;13(2):204-10. (PMID: 17237794) J Cell Biol. 2002 Jan 21;156(2):227-32. (PMID: 11790802) Am J Hum Genet. 2014 Dec 4;95(6):736-43. (PMID: 25434006) Hum Mol Genet. 2010 Dec 15;19(24):4790-8. (PMID: 20871099) Proc Natl Acad Sci U S A. 2015 Nov 10;112(45):14012-7. (PMID: 26494287) Am J Hum Genet. 2010 Nov 12;87(5):701-7. (PMID: 21055718) Nat Genet. 2007 Dec;39(12):1488-93. (PMID: 17994018) J Med Genet. 2016 Jul;53(7):457-64. (PMID: 27068007) Cardiovasc Res. 2010 Dec 1;88(3):520-9. (PMID: 20628007) Am J Med Genet A. 2015 Jun;167(6):1396-9. (PMID: 25899461) Eur J Oral Sci. 2017 Feb;125(1):8-17. (PMID: 28084688) J Vasc Surg. 1997 Mar;25(3):506-11. (PMID: 9081132) Nat Genet. 2012 Jul 08;44(8):916-21. (PMID: 22772371) Circ Res. 2016 Mar 18;118(6):928-34. (PMID: 26838787) Hum Mol Genet. 2015 Jun 1;24(11):3038-49. (PMID: 25669657) Nat Genet. 2011 Feb;43(2):121-6. (PMID: 21217753) J Surg Res. 2003 Jun 1;112(1):97-101. (PMID: 12873440) J Cell Physiol. 2012 Dec;227(12):3828-36. (PMID: 22495824) Nat Genet. 2004 Aug;36(8):855-60. (PMID: 15235604) Circ Res. 2011 Sep 2;109(6):680-6. (PMID: 21778426) Circ Res. 2017 Jun 9;120(12):1903-1915. (PMID: 28461455) Am J Hum Genet. 2013 Aug 8;93(2):398-404. (PMID: 23910461) FEBS Lett. 2002 Apr 24;517(1-3):277-80. (PMID: 12062452) Ann Thorac Surg. 2006 Oct;82(4):1400-5. (PMID: 16996941) Matrix Biol. 2015 Sep;47:44-53. (PMID: 25960419) J Cell Sci. 2010 Dec 15;123(Pt 24):4340-50. (PMID: 21098638) |
| معلومات مُعتمدة: | P01 HL110869 United States HL NHLBI NIH HHS; U54 HG006493 United States HG NHGRI NIH HHS; HHSN268201100037C United States HL NHLBI NIH HHS; R01 HL109942 United States HL NHLBI NIH HHS; UM1 HG006493 United States HG NHGRI NIH HHS; UL1 RR024148 United States RR NCRR NIH HHS; R01 HL062594 United States HL NHLBI NIH HHS; UL1 TR000371 United States TR NCATS NIH HHS |
| فهرسة مساهمة: | Keywords: LTBP3; amelogenesis imperfecta; aortic dissections; heritable thoracic aortic diseases |
| المشرفين على المادة: | 0 (LTBP3 protein, human) 0 (Latent TGF-beta Binding Proteins) |
| تواريخ الأحداث: | Date Created: 20180407 Date Completed: 20181211 Latest Revision: 20221207 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC5985335 |
| DOI: | 10.1016/j.ajhg.2018.03.002 |
| PMID: | 29625025 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1537-6605 |
|---|---|
| DOI: | 10.1016/j.ajhg.2018.03.002 |