Vascular Ehlers-Danlos Syndrome (vEDS) is a syndrome characterised by thin, translucent skin, easy bruising, hypermobility of small joints, aged appearance of hands, characteristic facial features (such as thin lips, small chin, thin nose & large eyes), and fragile blood vessels. Fragile blood vessels are particularly serious as they increase the risk of complications such as arterial ruptures and aneurysms.

vEDS is a genetic condition caused by autosomal dominant pathogenic variants in the gene COL3A1, which is predicted to affect between 1/50,000 and 1/200,000 people. The COL3A1 gene plays a role in the production of type III collagen. Pathogenic variants to this gene results in disrupted production of this collagen, leading to less functionally efficient connective tissue, especially within blood vessels and hollow organs (such as the intestine). 

Zebrafish have two closely related genes to the human COL3A1 - col1a2 and col5a1. We will generate zebrafish genetic mutants of these two genes to model human vEDS in zebrafish. These fish will be characterised with a variety of laboratory techniques, allowing us  to develop a better understanding of vEDS. Ultimately, we aim to develop novel & effective therapeutic approaches for vEDS to improve clinical management and the quality of life for vEDS patients.

Neuroblastoma Amplified Sequence (NBAS) is thought to be involved in Collagen I secretion, although the precise mechanism remains unknown. Biallelic pathogenic variants in NBAS are associated with atypical Osteogenesis Imperfecta (OI), characterised by short stature, bone deformities, low bone mineral density, and frequent fractures. A recurrent, homozygous NBAS variant, c.5714G>A, p.Arg1914His (R1914H), results in SOPH syndrome (Short stature, Optic atrophy, Pelger-Huet anomaly). Recent studies suggest that NBAS may contribute to a multisystem phenotype affecting multiple tissues. This phenotypic variability highlights the importance of understanding the NBAS function.

Our research is focused on two zebrafish models of nbas: a disease-specific missense R1914H variant and a nonsense sa16290 mutant. Detailed characterisation of these two zebrafish lines will enable us to investigate NBAS’s role in the collagen secretion pathway, elucidate disease mechanisms, and identify potential drug candidates that could alleviate symptoms in patients with NBAS-related disorders.

In 1987, Cole and Carpenter reported two cases of a divergent phenotype, resembling the one of OI with additional distinct features. Both patients displayed multiple fractures and distinctive dysmorphic attributes, including ocular proptosis, frontal bossing, short stature and bone deformities.  This pattern in the phenotype has been since known as Cole-Carpenter Syndrome. Genetic analysis uncovered a heterozygous c.1178A>G (p.Tyr393Cys) variant in exon 9 of the P4HB gene, responsible for encoding a protein disulphide isomerase (PDI). PDI is required for disulphide-bond formation, facilitating protein folding. The substitution is thought to interfere with the release of collagen from the enzyme, disrupting its folding, and leading to ER stress.  

We have generated and characterised a disease-specific knock-in zebrafish model of the Cole-Carpenter Syndrome. Our current research is focused on establishing a robust drug-screening readout to ultimately identify successful drug candidates.

Our lab is working on developing HNRNPU-NDD zebrafish as a novel model for understanding the molecular and functional impacts of the disorder. This will allow us to better understand the mechanisms of disease and disease phenotypes, where previous animal models have fallen short. We believe zebrafish are more able to fully recapitulate the phenotypes seen in HNRNPU-NDD, including its effects on brain development. Currently, we have developed and are characterising a CRISPR knockout line of HNRNPU A and B. Through these models, we can better understand the disorder and thus explore gene and gene-directed therapies and how they would impact a developing brain.