Universität zu Köln

Pottie, Lore ORCID: 0000-0001-5102-975X, Adamo, Christin S. ORCID: 0000-0002-8560-6153, Beyens, Aude, Luetke, Steffen, Tapaneeyaphan, Piyanoot, De Clercq, Adelbert ORCID: 0000-0003-2670-1684, Salmon, Phil L., De Rycke, Riet, Gezdirici, Alper ORCID: 0000-0002-2432-9279, Gulec, Elif Yilmaz, Khan, Naz, Urquhart, Jill E., Newman, William G., Metcalfe, Kay, Efthymiou, Stephanie ORCID: 0000-0003-4900-9877, Maroofian, Reza, Anwar, Najwa, Maqbool, Shazia, Rahman, Fatima, Altweijri, Ikhlass, Alsaleh, Monerah, Abdullah, Sawsan Mohamed, Al-Owain, Mohammad, Hashem, Mais, Houlden, Henry, Alkuraya, Fowzan S., Sips, Patrick ORCID: 0000-0001-9241-5980, Sengle, Gerhard and Callewaert, Bert ORCID: 0000-0002-9743-4205 (2021). Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome. Am. J. Hum. Genet., 108 (6). S. 1095 - 1115. CAMBRIDGE: CELL PRESS. ISSN 1537-6605

Full text not available from this repository.

Abstract

Latent transforming growth factor beta (TGF beta)-binding proteins (LTBPs) are microfibril-associated proteins essential for anchoring TGF beta in the extracellular matrix (ECM) as well as for correct assembly of ECM components. Variants in LTBP2, LTBP3, and LTBP4 have been identified in several autosomal recessive Mendelian disorders with skeletal abnormalities with or without impaired development of elastin-rich tissues. Thus far, the human phenotype associated with LTBP1 deficiency has remained enigmatic. In this study, we report homozygous premature truncating LTBP1 variants in eight affected individuals from four unrelated consanguineous families. Affected individuals present with connective tissue features (cutis laxa and inguinal hernia), craniofacial dysmorphology, variable heart defects, and prominent skeletal features (craniosynostosis, short stature, brachydactyly, and syndactyly). In vitro studies on proband-derived dermal fibroblasts indicate distinct molecular mechanisms depending on the position of the variant in LTBP1. C-terminal variants lead to an altered LTBP1 loosely anchored in the microfibrillar network and cause increased ECM deposition in cultured fibroblasts associated with excessive TGF beta growth factor activation and signaling. In contrast, N-terminal truncation results in a loss of LTBP1 that does not alter TGF beta levels or ECM assembly. In vivo validation with two independent zebrafish lines carrying mutations in ltbp1 induce abnormal collagen fibrillogenesis in skin and intervertebral ligaments and ectopic bone formation on the vertebrae. In addition, one of the mutant zebrafish lines shows voluminous and hypo-mineralized vertebrae. Overall, our findings in humans and zebrafish show that LTBP1 function is crucial for skin and bone ECM assembly and homeostasis.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Pottie, Lore UNSPECIFIED orcid.org/0000-0001-5102-975X UNSPECIFIED Adamo, Christin S. UNSPECIFIED orcid.org/0000-0002-8560-6153 UNSPECIFIED Beyens, Aude UNSPECIFIED UNSPECIFIED UNSPECIFIED Luetke, Steffen UNSPECIFIED UNSPECIFIED UNSPECIFIED Tapaneeyaphan, Piyanoot UNSPECIFIED UNSPECIFIED UNSPECIFIED De Clercq, Adelbert UNSPECIFIED orcid.org/0000-0003-2670-1684 UNSPECIFIED Salmon, Phil L. UNSPECIFIED UNSPECIFIED UNSPECIFIED De Rycke, Riet UNSPECIFIED UNSPECIFIED UNSPECIFIED Gezdirici, Alper UNSPECIFIED orcid.org/0000-0002-2432-9279 UNSPECIFIED Gulec, Elif Yilmaz UNSPECIFIED UNSPECIFIED UNSPECIFIED Khan, Naz UNSPECIFIED UNSPECIFIED UNSPECIFIED Urquhart, Jill E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Newman, William G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Metcalfe, Kay UNSPECIFIED UNSPECIFIED UNSPECIFIED Efthymiou, Stephanie UNSPECIFIED orcid.org/0000-0003-4900-9877 UNSPECIFIED Maroofian, Reza UNSPECIFIED UNSPECIFIED UNSPECIFIED Anwar, Najwa UNSPECIFIED UNSPECIFIED UNSPECIFIED Maqbool, Shazia UNSPECIFIED UNSPECIFIED UNSPECIFIED Rahman, Fatima UNSPECIFIED UNSPECIFIED UNSPECIFIED Altweijri, Ikhlass UNSPECIFIED UNSPECIFIED UNSPECIFIED Alsaleh, Monerah UNSPECIFIED UNSPECIFIED UNSPECIFIED Abdullah, Sawsan Mohamed UNSPECIFIED UNSPECIFIED UNSPECIFIED Al-Owain, Mohammad UNSPECIFIED UNSPECIFIED UNSPECIFIED Hashem, Mais UNSPECIFIED UNSPECIFIED UNSPECIFIED Houlden, Henry UNSPECIFIED UNSPECIFIED UNSPECIFIED Alkuraya, Fowzan S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sips, Patrick UNSPECIFIED orcid.org/0000-0001-9241-5980 UNSPECIFIED Sengle, Gerhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Callewaert, Bert UNSPECIFIED orcid.org/0000-0002-9743-4205 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-602466
DOI:	10.1016/j.ajhg.2021.04.016
Journal or Publication Title:	Am. J. Hum. Genet.
Volume:	108
Number:	6
Page Range:	S. 1095 - 1115
Date:	2021
Publisher:	CELL PRESS
Place of Publication:	CAMBRIDGE
ISSN:	1537-6605
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BINDING-PROTEIN 4; FIBRILLIN-CONTAINING MICROFIBRILS; TGF-BETA; GROWTH-FACTOR; MARFAN-SYNDROME; BONE; MUTATIONS; FIBULIN-4; ZEBRAFISH; ELASTOGENESIS Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/60246