Sanne D'hondt

Bio: Sanne D'hondt is an academic researcher from Ghent University Hospital. The author has contributed to research in topics: Cilium & Neural crest. The author has an hindex of 4, co-authored 5 publications receiving 185 citations. Previous affiliations of Sanne D'hondt include Ghent University.

Deficiency for the ER-stress transducer OASIS causes severe recessive osteogenesis imperfecta in humans

Abstract: Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous brittle bone disorder. Whereas dominant OI is mostly due to heterozygous mutations in either COL1A1 or COL1A2, encoding type I procollagen, recessive OI is caused by biallelic mutations in genes encoding proteins involved in type I procollagen processing or chaperoning. Hitherto, some OI cases remain molecularly unexplained. We detected a homozygous genomic deletion of CREB3L1 in a family with severe OI. CREB3L1 encodes OASIS, an endoplasmic reticulum-stress transducer that regulates type I procollagen expression during murine bone formation. This is the first report linking CREB3L1 to human recessive OI, thereby expanding the OI gene spectrum.

Genetic Defects in TAPT1 Disrupt Ciliogenesis and Cause a Complex Lethal Osteochondrodysplasia

Abstract: The evolutionarily conserved transmembrane anterior posterior transformation 1 protein, encoded by TAPT1, is involved in murine axial skeletal patterning, but its cellular function remains unknown. Our study demonstrates that TAPT1 mutations underlie a complex congenital syndrome, showing clinical overlap between lethal skeletal dysplasias and ciliopathies. This syndrome is characterized by fetal lethality, severe hypomineralization of the entire skeleton and intra-uterine fractures, and multiple congenital developmental anomalies affecting the brain, lungs, and kidneys. We establish that wild-type TAPT1 localizes to the centrosome and/or ciliary basal body, whereas defective TAPT1 mislocalizes to the cytoplasm and disrupts Golgi morphology and trafficking and normal primary cilium formation. Knockdown of tapt1b in zebrafish induces severe craniofacial cartilage malformations and delayed ossification, which is shown to be associated with aberrant differentiation of cranial neural crest cells.

Aberrant binding of mutant HSP47 affects posttranslational modification of type I collagen and leads to osteogenesis imperfecta.

Abstract: Heat shock protein 47 (HSP47), encoded by the SERPINH1 gene, is a molecular chaperone essential for correct folding of collagens We report a homozygous p(R222S) substitution in HSP47 in a child with severe osteogenesis imperfecta leading to early demise pR222 is a highly conserved residue located within the collagen interacting surface of HSP47 Binding assays show a significantly reduced affinity of HSP47-R222S for type I collagen This altered interaction leads to posttranslational overmodification of type I procollagen produced by dermal fibroblasts, with increased glycosylation and/or hydroxylation of lysine and proline residues as shown by mass spectrometry Since we also observed a normal intracellular folding and secretion rate of type I procollagen, this overmodification cannot be explained by prolonged exposure of the procollagen molecules to the modifying hydroxyl- and glycosyltransferases, as is commonly observed in other types of OI We found significant upregulation of several molecular chaperones and enzymes involved in procollagen modification and folding on Western blot and RT-qPCR In addition, we showed that an imbalance in binding of HSP47-R222S to unfolded type I collagen chains in a gelatin sepharose pulldown assay results in increased binding of other chaperones and modifying enzymes The elevated expression and binding of this molecular ensemble to type I procollagen suggests a compensatory mechanism for the aberrant binding of HSP47-R222S, eventually leading to overmodification of type I procollagen chains Together, these results illustrate the importance of HSP47 for proper posttranslational modification and provide insights into the molecular pathomechanisms of the p(R222S) alteration in HSP47, which leads to a severe OI phenotype

Osteogenesis imperfecta: Clinical diagnosis, nomenclature and severity assessment

Abstract: Recently, the genetic heterogeneity in osteogenesis imperfecta (OI), proposed in 1979 by Sillence et al., has been confirmed with molecular genetic studies. At present, 17 genetic causes of OI and closely related disorders have been identified and it is expected that more will follow. Unlike most reviews that have been published in the last decade on the genetic causes and biochemical processes leading to OI, this review focuses on the clinical classification of OI and elaborates on the newly proposed OI classification from 2010, which returned to a descriptive and numerical grouping of five OI syndromic groups. The new OI nomenclature and the pre-and postnatal severity assessment introduced in this review, emphasize the importance of phenotyping in order to diagnose, classify, and assess severity of OI. This will provide patients and their families with insight into the probable course of the disorder and it will allow physicians to evaluate the effect of therapy. A careful clinical description in combination with knowledge of the specific molecular genetic cause is the starting point for development and assessment of therapy in patients with heritable disorders including OI. © 2014 The Authors. American Journal of Medical Genetics Published by Wiley Periodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution–NonCommercial–NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Clinical and Genetic Features of Ehlers-Danlos Syndrome Type IV, the Vascular Type

Abstract: Background Ehlers–Danlos syndrome type IV, the vascular type, results from mutations in the gene for type III procollagen (COL3A1). Affected patients are at risk for arterial, bowel, and uterine rupture, but the timing of these events, their frequency, and the course of the disease are not well documented. Methods We reviewed the clinical and family histories of and medical and surgical complications in 220 index patients with biochemically confirmed Ehlers–Danlos syndrome type IV and 199 of their affected relatives. We identified the underlying COL3A1 mutation in 135 index patients. Results Complications were rare in childhood; 25 percent of the index patients had a first complication by the age of 20 years, and more than 80 percent had had at least one complication by the age of 40. The calculated median survival of the entire cohort was 48 years. Most deaths resulted from arterial rupture. Bowel rupture, which often involved the sigmoid colon, accounted for about a quarter of complications but rarely l...

Genes Associated with Thoracic Aortic Aneurysm and Dissection: 2018 Update and Clinical Implications.

Abstract: Thoracic aortic aneurysms, with an estimated prevalence in the general population of 1%, are potentially lethal, via rupture or dissection Over the prior two decades, there has been an exponential increase in our understanding of the genetics of thoracic aortic aneurysm and/or dissection (TAAD) To date, 30 genes have been shown to be associated with the development of TAAD and ∼30% of individuals with nonsyndromic familial TAAD have a pathogenic mutation in one of these genes This review represents the authors' yearly update summarizing the genes associated with TAAD, including implications for the surgical treatment of TAAD Molecular genetics will continue to revolutionize the approach to patients afflicted with this devastating disease, permitting the application of genetically personalized aortic care

The Ehlers-Danlos syndromes.

Abstract: The Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary disorders of connective tissue, with common features including joint hypermobility, soft and hyperextensible skin, abnormal wound healing and easy bruising. Fourteen different types of EDS are recognized, of which the molecular cause is known for 13 types. These types are caused by variants in 20 different genes, the majority of which encode the fibrillar collagen types I, III and V, modifying or processing enzymes for those proteins, and enzymes that can modify glycosaminoglycan chains of proteoglycans. For the hypermobile type of EDS, the molecular underpinnings remain unknown. As connective tissue is ubiquitously distributed throughout the body, manifestations of the different types of EDS are present, to varying degrees, in virtually every organ system. This can make these disorders particularly challenging to diagnose and manage. Management consists of a care team responsible for surveillance of major and organ-specific complications (for example, arterial aneurysm and dissection), integrated physical medicine and rehabilitation. No specific medical or genetic therapies are available for any type of EDS.