Zebrafish type I collagen mutants faithfully recapitulate human type I collagenopathies

Abstract

The type I collagenopathies are a group of heterogeneous connective tissue disorders, that are caused by mutations in the genes encoding type I collagen and include specific forms of Osteogenesis Imperfecta (OI) and the Ehlers-Danlos syndrome (EDS). These disorders present with a broad disease spectrum and large clinical variability of which the underlying genetic basis is still poorly understood. In this study, we systematically analyzed skeletal phenotypes in a large set of zebrafish, with diverse mutations in the genes encoding type I collagen, representing different genetic forms of human OI, and the first zebrafish model of human EDS, which harbors characteristic defects in the soft connective tissues. Furthermore, we provide insight into how zebrafish and human type I collagen are compositionally and functionally related, which is relevant in the interpretation of human type I collagen related disease models. Our studies reveal a high degree of inter-genotype variability in phenotypic expressivity that closely correlates with associated OI severity. Further, we demonstrate the potential for select mutations to give rise to variable phenotypic penetrance, mirroring the clinical variability associated with human disease pathology. Therefore, our work suggests the potential for zebrafish to aid in identifying unknown genetic modifiers and mechanisms underlying the phenotypic variability in OI and related disorders. This will improve diagnostic strategies and enable the discovery of new targetable pathways for pharmacological intervention

Neuronal NADPH oxidase 2 regulates growth cone guidance downstream of slit2/robo2

“…Genes that are in the same signaling pathway are typically not expected to show an enhanced phenotype in double homozygous knockouts or mutants when compared to individual gene knockouts/mutants. On the contrary, weak phenotypes produced by heterozygotes or weaker alleles of different genes in the same pathway can be enhanced when combined with each other (Gistelinck et al., 2018; Iwanami et al., 2016). Here, we tested our hypothesis that Nox2 and Robo2 are in the same pathway with astray/nox2 double heterozygous mutants along with individual heterozygous and homozygous mutants (Figure 4).…”

Exercise‐induced lordosis in zebrafish Danio rerio (Hamilton, 1822)

“…Teleosts have been widely used as animal models to define the underlying molecular basis of human bone diseases ( e.g ., Fjelldal et al ., 2004; Gistelinck et al ., 2018; Gorman & Breden, 2007; Mackay et al ., 2013). In the present study, a method for the induction of vertebral abnormalities in wild‐type zebrafish with initially normal phenotype was developed.…”

“…Anatomy and development of the skeleton in zebrafish are well characterized (Bensimon‐Brito et al ., 2012; Bird & Mabee, 2003; Christou et al ., 2018; Ferreri et al ., 2000; Parichy et al ., 2009). Today zebrafish is considered as a vertebrate model for human bone diseases ( e.g ., Clement et al ., 2008; Gistelinck et al ., 2016; Gistelinck et al ., 2018; Mackay et al ., 2013; Witten et al ., 2017). Moreover, musculoskeletal responses to exercise have been studied in zebrafish (Fiaz et al ., 2012; Palstra et al ., 2010; Suniaga et al ., 2018).…”

b3galt6knock-out zebrafish recapitulate β3GalT6-deficiency disorders in human and reveal a trisaccharide proteoglycan linkage region

“…Wild-type (AB strain) and b3galt6 knock-out zebrafish lines were reared and maintained by standard protocols [48]. All animal studies were performed in agreement with EU Directive 2010/63/EU for animals, permit number: ECD 16/18.…”