2. Academic Validation
  3. Bi-allelic premature truncating variants in LTBP1 cause cutis laxa syndrome

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

  • Am J Hum Genet. 2021 Jun 3;108(6):1095-1114. doi: 10.1016/j.ajhg.2021.04.016.
Lore Pottie 1,  Christin S Adamo 2,  Aude Beyens 3,  Steffen Lütke 2,  Piyanoot Tapaneeyaphan 1,  Adelbert De Clercq 1,  Phil L Salmon 4,  Riet De Rycke 5,  Alper Gezdirici 6,  Elif Yilmaz Gulec 7,  Naz Khan 8,  Jill E Urquhart 8,  William G Newman 8,  Kay Metcalfe 9,  Stephanie Efthymiou 10,  Reza Maroofian 10,  Najwa Anwar 11,  Shazia Maqbool 11,  Fatima Rahman 11,  Ikhlass Altweijri 12,  Monerah Alsaleh 13,  Sawsan Mohamed Abdullah 14,  Mohammad Al-Owain 15,  Mais Hashem 14,  Henry Houlden 10,  Fowzan S Alkuraya 15,  Patrick Sips 1,  Gerhard Sengle 16,  Bert Callewaert 17
Affiliations

Affiliations

  • 1 Center for Medical Genetics Ghent, Ghent University Hospital, Ghent 9000, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent 9000, Belgium.
  • 2 Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany; Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany.
  • 3 Center for Medical Genetics Ghent, Ghent University Hospital, Ghent 9000, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent 9000, Belgium; Department of Dermatology, Ghent University Hospital, Ghent 9000, Belgium.
  • 4 Bruker microCT, Kontich 2550, Belgium.
  • 5 Department of Biomedical Molecular Biology, Ghent University, Ghent 9052, Belgium; VIB Center for Inflammation Research, Ghent 9052, Belgium; Ghent University Expertise Centre for Transmission Electron Microscopy and VIB Bioimaging Core, Ghent 9052, Belgium.
  • 6 Department of Medical Genetics, Basaksehir Cam and Sakura City Hospital, Istanbul 34480, Turkey.
  • 7 Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, Health Sciences University, Istanbul 34303, Turkey.
  • 8 Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK.
  • 9 Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester M13 9WL, UK.
  • 10 Department of Neuromuscular Disorders, UCL Institute of Neurology, London WC1N 3BG, UK.
  • 11 Development and Behavioral Pediatrics Department, Institute of Child Health and The Children Hospital, Lahore 54000, Pakistan.
  • 12 Department of Neurosurgery, King Khalid University Hospital, Riyadh 11211, Saudi Arabia.
  • 13 Heart Centre, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 14 Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
  • 15 Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia; Department of Anatomy and Cell Biology, College of Medicine, Alfaisal University, Riyadh 11211, Saudi Arabia.
  • 16 Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany; Department of Pediatrics and Adolescent Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne 50931, Germany; Center for Molecular Medicine Cologne, University of Cologne, Robert-Koch-Street 21, Cologne 50931, Germany; Cologne Center for Musculoskeletal Biomechanics, Cologne 50931, Germany.
  • 17 Center for Medical Genetics Ghent, Ghent University Hospital, Ghent 9000, Belgium; Department of Biomolecular Medicine, Ghent University, Ghent 9000, Belgium. Electronic address: bert.callewaert@ugent.be.
PMID: 33991472 DOI: 10.1016/j.ajhg.2021.04.016
Abstract

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.

Keywords

Danio rerio; LTBP1, transforming growth factor beta; collagen fibrillogenesis; craniosynostosis; cutis laxa syndrome; extracellular matrix; short stature; tissue mineral density.

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