Background: Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1/15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcomes.
Methodology and results: Trio whole exome sequencing in patients with OI identified, in two patients, compound heterozygous mutations in NBAS (Neuroblastoma amplified sequence). Patient 1: c.5741G>A p.(Arg1914His); c.3010C>T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring bisphosphonate treatment, developmental delay and immunodeficiency. A transiliac bone biopsy, following recurrent low-trauma fractures, demonstrated osteoporosis with high bone turnover with marked sub-periosteal bone resorption, different to classical OI. Patient 2: c.5741G>A p.(Arg1914His); c.2032C>T p.(Glu678*) in a 5-year old boy with bone fragility, developmental delay and immunodeficiency. Studies in human patient fibroblasts (hpf) showed reduced collagen expression, compared to control cells; RNAseq studies, in bone cells showed NBAS expression in osteoblasts and osteocytes of rodents and primates; Western blot analysis shows reduced level of NBAS protein in hpf, compared to control cells, implying that NBAS mutations compromise the stability of NBAS protein. CRISPR-Cas9 technology has been used to generate stable knockout NBAS cell lines in human SAOS2 osteoblast cells.
Discussion: These findings provide proof-of-concept that NBAS mutations have mechanistic effects in bone, and NBAS mutations are a novel cause of bone fragility, distinguishable from Classical OI. Since NBAS has been proposed to function in the nonsense mediated decay (NMD) pathway and is also part of the Golgi-ER transport, the effect on bone fragility may be attributable to either pathway in isolation or to both. In our clinical practice, patients with NBAS variants have responded positively to bisphosphonate treatment, with marked improvement in their bone health and quality of life.
Conclusions: Here we report on NBAS mutations as a novel cause of bone fragility. Further studies are ongoing to elucidate the precise mechanism of action of NBAS and its role in bone fragility. We have since identified more patients with NBAS variants and will explore the phenotypic variability with special attention to their effect on bone health.
Disclosure: The authors declared no competing interests.