Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome.

Latent transforming growth factor β (TGFβ)-binding proteins (LTBPs) are microfibril-associated proteins essential for anchoring TGFβ 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 TGFβ growth factor activation and signaling. In contrast, N-terminal truncation results in a loss of LTBP1 that does not alter TGFβ 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. Copyright © 2021 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Citation

Lore Pottie, Christin S Adamo, Aude Beyens, Steffen Lütke, Piyanoot Tapaneeyaphan, Adelbert De Clercq, Phil L Salmon, Riet De Rycke, Alper Gezdirici, Elif Yilmaz Gulec, Naz Khan, Jill E Urquhart, William G Newman, Kay Metcalfe, Stephanie Efthymiou, Reza Maroofian, Najwa Anwar, Shazia Maqbool, Fatima Rahman, Ikhlass Altweijri, Monerah Alsaleh, Sawsan Mohamed Abdullah, Mohammad Al-Owain, Mais Hashem, Henry Houlden, Fowzan S Alkuraya, Patrick Sips, Gerhard Sengle, Bert Callewaert. Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome. American journal of human genetics. 2021 Jun 03;108(6):1095-1114

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PMID: 33991472

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