SignificanceType I collagenopathies are a heterogenous group of connective tissue disorders, caused by genetic defects in type I collagen. Inherent to these disorders is a large clinical variability, of which the underlying molecular basis remains undefined. By systematically analyzing skeletal phenotypes in a large set of type I collagen zebrafish mutants, we show that zebrafish models are able to both genocopy and phenocopy different forms of human type I collagenopathies, arguing for a similar pathogenetic basis. This study illustrates the future potential of zebrafish as a tool to further dissect the molecular basis of phenotypic variability in human type I collagenopathies, to improve diagnostic strategies as well as promote the discovery of new targetable pathways for pharmacological intervention of these disorders.
The 2017 classification of Ehlers‐Danlos syndromes (EDS) identifies three types associated with causative variants in COL1A1/COL1A2 and distinct from osteogenesis imperfecta (OI). Previously, patients have been described with variable features of both disorders, and causative variants in COL1A1/COL1A2; but this phenotype has not been included in the current classification. Here, we expand and re‐define this OI/EDS overlap as a missing EDS type. Twenty‐one individuals from 13 families were reported, in whom COL1A1/COL1A2 variants were found after a suspicion of EDS. None of them could be classified as affected by OI or by any of the three recognized EDS variants associated with COL1A1/COL1A2. This phenotype is dominated by EDS‐related features. OI‐related features were limited to mildly reduced bone mass, occasional fractures and short stature. Eight COL1A1/COL1A2 variants were novel and five recurrent with a predominance of glycine substitutions affecting residues within the procollagen N‐proteinase cleavage site of α1(I) and α2(I) procollagens. Selected variants were investigated by biochemical, ultrastructural and immunofluorescence studies. The pattern of observed changes in the dermis and in vitro for selected variants was more typical of EDS rather than OI. Our findings indicate the existence of a wider recognizable spectrum associated with COL1A1/COL1A2.
Proteoglycans are among the most abundant and structurally complex biomacromolecules and play critical roles in connective tissues. They are composed of a core protein onto which glycosaminoglycan (GAG) side chains are attached via a linker region. Biallelic mutations in B3GALT6, encoding one of the linker region glycosyltransferases, are known to cause either spondyloepimetaphyseal dysplasia (SEMD) or a severe pleiotropic form of Ehlers-Danlos syndromes (EDS). This study provides clinical, molecular and biochemical data on 12 patients with biallelic B3GALT6 mutations. Notably, all patients have features of both EDS and SEMD. In addition, some patients have severe and potential life-threatening complications such as aortic dilatation and aneurysm, cervical spine instability and respiratory insufficiency. Whole-exome sequencing, next generation panel sequencing and direct sequencing identified biallelic B3GALT6 mutations in all patients. We show that these mutations reduce the amount of β3GalT6 protein and lead to a complete loss of galactosyltransferase activity. In turn, this leads to deficient GAG synthesis, and ultrastructural abnormalities in collagen fibril organization. In conclusion, this study redefines the phenotype associated with B3GALT6 mutations on the basis of clinical, molecular and biochemical data in 12 patients, and provides an in-depth assessment of β3GalT6 activity and GAG synthesis to better understand this rare condition.
The disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family of metalloproteases consists of 19 members. These enzymes play an important role in the turnover of extracellular matrix proteins in various tissues and their altered regulation has been implicated in diseases such as cancer, arthritis and atherosclerosis. Unlike other metalloproteinases, ADAMTS members demonstrate a narrow substrate specificity due to the various exosites located in the C-terminal regions of the enzymes, which influence protein recognition and matrix localization. The tight substrate specificity exhibited by ADAMTS enzymes makes them potentially safe pharmaceutical targets, as selective inhibitors designed for each member will result in the inhibition or cleavage of only a limited number of proteins. With the recent elucidation of crystal structures for ADAMTS-1, -4 and -5, the design of potent and selective small molecule inhibitors is underway and will lead to drug candidates for evaluation in clinical trials in the next 5-10 years.
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