Expanding genotypic and phenotypic spectrums of LTBP3 variants in dental anomalies and short stature syndrome.
TGFB
atrial septal defect
congenital heart diseases
interatrial septal aneurysm
root defects
tooth eruption
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
revised:
23
03
2022
received:
26
02
2022
accepted:
24
03
2022
pubmed:
31
3
2022
medline:
16
6
2022
entrez:
30
3
2022
Statut:
ppublish
Résumé
Mutations in LTBP3 are associated with Dental Anomalies and Short Stature syndrome (DASS; MIM 601216), which is characterized by hypoplastic type amelogenesis imperfecta, hypodontia, underdeveloped maxilla, short stature, brachyolmia, aneurysm and dissection of the thoracic aorta. Here we report a novel (p.Arg545ProfsTer22) and a recurrent (c.3107-2A > G) LTBP3 variants, in a Turkish family affected with DASS. The proband, who carried compound heterozygous variant c.3107-2A > G, p.Arg545ProfsTer22, was most severely affected with DASS. The proband's father, who carried the heterozygous variant c.3107-2A > G had short stature and prognathic mandible. The mother and brother of the proband carried the heterozygous variant p.Arg545ProfsTer22, but only the mother showed any DASS characteristics. The c.3107-2A > G and the p.Arg545ProfsTer22 variants are expected to result in abnormal LTPB3 protein, failure of TGFβ-LAP-LTBP3 complex formation, and subsequent disruption of TGFβ secretion and activation. This is the first report of heterozygous carriers of LTBP3 variants showing phenotypes. The new findings of DASS found in this family include taurodontism, single-rooted molars, abnormal dentin, calcified dental pulp blood vessels, prognathic mandible, failure of mandibular tooth eruption, interatrial septal aneurysm, secundum atrial septal defect, tricuspid valve prolapse, and a recurrent glenohumeral joint dislocation.
Substances chimiques
LTBP3 protein, human
0
Latent TGF-beta Binding Proteins
0
Transforming Growth Factor beta
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
66-71Informations de copyright
© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Dabovic B, Chen Y, Colarossi C, et al. Bone abnormalities in latent TGF-[beta] binding protein (Ltbp)-3-null mice indicate a role for Ltbp-3 in modulating TGF-[beta] bioavailability. J Cell Biol. 2002;156(2):227-232. doi:10.1083/jcb.200111080
Huckert M, Stoetzel C, Morkmued S, et al. Mutations in the latent TGF-beta binding protein 3 (LTBP3) gene cause brachyolmia with amelogenesis imperfecta. Hum Mol Genet. 2015;24(11):3038-3049. doi:10.1093/hmg/ddv053
Guo DC, Regalado ES, Pinard A, et al. LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections. Am J Hum Genet. 2018;102(4):706-712. doi:10.1016/j.ajhg.2018.03.002
Noor A, Windpassinger C, Vitcu I, et al. Oligodontia is caused by mutation in LTBP3, the gene encoding latent TGF-beta binding protein 3. Am J Hum Genet. 2009;84(4):519-523. doi:10.1016/j.ajhg.2009.03.007
Intarak N, Theerapanon T, Thaweesapphithak S, Suphapeetiporn K, Porntaveetus T, Shotelersuk V. Genotype-phenotype correlation and expansion of orodental anomalies in LTBP3-related disorders. Mol Genet Genomics. 2019;294(3):773-787. doi:10.1007/s00438-019-01547-x
Abramowicz A, Gos M. Splicing mutations in human genetic disorders: examples, detection, and confirmation. J Appl Genet. 2018;59(3):253-268.
Morkmued S, Hemmerle J, Mathieu E, et al. Enamel and dental anomalies in latent-transforming growth factor beta-binding protein 3 mutant mice. Eur J Oral Sci. 2017;125(1):8-17. doi:10.1111/eos.12328
Wu M, Chen G, Li YP. TGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016;4:16009. doi:10.1038/boneres.2016.9
Izumida E, Suzawa T, Miyamoto Y, et al. Functional analysis of PTH1R variants found in primary failure of eruption. J Dent Res. 2020;99(4):429-436. doi:10.1177/0022034520901731
Wang J, Feng JQ. Signaling pathways critical for tooth root formation. J Dent Res. 2017;96(11):1221-1228. doi:10.1177/0022034517717478
Inamoto S, Kwartler CS, Lafont AL, et al. TGFBR2 mutations alter smooth muscle cell phenotype and predispose to thoracic aortic aneurysms and dissections. Cardiovasc Res. 2010;88(3):520-529. doi:10.1093/cvr/cvq230
Combs MD, Yutzey KE. Heart valve development: regulatory networks in development and disease. Circ Res. 2009;105(5):408-421. doi:10.1161/CIRCRESAHA.109.201566
Renard M, Callewaert B, Malfait F, et al. Thoracic aortic-aneurysm and dissection in association with significant mitral valve disease caused by mutations in TGFB2. Int J Cardiol. 2013;165(3):584-587. doi:10.1016/j.ijcard.2012.09.029
Burns T, Yang Y, Hiriart E, Wessels A. The dorsal mesenchymal protrusion and the pathogenesis of atrioventricular septal defects. J Cardiovasc Dev Dis. 2016;3(4):29. doi:10.3390/jcdd3040029