Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 108, Issue 6, Pages 1095-1114Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2021.04.016
Keywords
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Categories
Funding
- Special Research Fund of Ghent University [01N04516C]
- Methusalem grant from the Special Research Fund of Ghent University [BOFMET2015000401]
- Fund for Scientific Research [G035620N]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [73111208, 397484323, FOR2722/C2]
- European Union [794365]
- Wellcome Trust
- National Institute for Health Research University College London Hospitals Biomedical Research Centre
- MRC [MR/S01165X/1, MR/S005021/1, G0601943]
- Rosetree Trust
- Ataxia UK
- MSA Trust
- Brain Research UK
- Sparks GOSH Charity
- Muscular Dystrophy UK (MDUK)
- Muscular Dystrophy Association (MDA USA)
- Manchester NIHR BRC [IS-BRC-1215-20007]
- [WT093205 MA]
- [WT104033AIA]
- Medical Research Council [G0601943, MR/S005021/1, MR/S01165X/1] Funding Source: researchfish
- Rosetrees Trust [PGL19-2 10118] Funding Source: researchfish
- Marie Curie Actions (MSCA) [794365] Funding Source: Marie Curie Actions (MSCA)
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Variants in LTBP1 result in a range of connective tissue and skeletal abnormalities in patients, particularly affecting the crucial processes of skin and bone ECM assembly and homeostasis.
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.
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