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 disulfide isomerase (PDI). PDI is required for disulfide-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.

We are working towards developing phenotypic assays to facilitate molecular and cellular characterisation of OI phenotype using iPSC cell lines. We hypothesise that access to disease-relevant cells with patient-specific variants will provide the most representative models of OI, thus allowing us to set up reliable assays for therapeutic discovery. We are deriving iPSCs from our existing banks of OI patients’ fibroblasts and differentiating these into osteoblasts. We plan to set up a phenotypic assay as a proof-of-principle for future high-throughput drug discovery efforts and in-depth mechanistic studies.