Compound heterozygous variants in NBAS as a cause of atypical osteogenesis imperfecta

Abstract

Background Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 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 outcome and patient benefit. Report Whole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (Neuroblastoma amplified sequence). Patient 1: NBAS c.5741G>A p.(Arg1914His); c.3010C>T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G>A p.(Arg1914His); c.2032C>T p.(Glu678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency. Discussion Homozygous missense NBAS variants cause SOPH syndrome (Short stature; Optic atrophy; Pelger-Huet anomaly), the same missense variant was found in our patients on one allele and a nonsense variant in the other allele. Recent literature suggests a multi-system phenotype. In this study, patient fibroblasts have shown reduced collagen expression, compared to control cells and RNAseq studies, in bone cells show that NBAS is expressed in osteoblasts and osteocytes of rodents and primates. These findings provide proof-of-concept that NBAS mutations have mechanistic effects in bone, and that NBAS variants are a novel cause of bone fragility, which is distinguishable from ‘Classical’ OI. Conclusions Here we report on variants in NBAS, as a cause of bone fragility in humans, and expand the phenotypic spectrum associated with NBAS. We explore the mechanism underlying NBAS and the striking skeletal phenotype in our patients.

TANGO1 builds a machine for collagen export by recruiting and spatially organizing COPII, tethers and membranes

“…One component of the MTC (RINT1) was also identified in our screen for genes required for protein secretion ( Bard et al, 2006 ). Mutations in another component NBAS, are linked to dysregulated collagen secretion in atypical osteogenesis imperfecta ( DDD Study et al, 2017 ).…”

COPII-dependent ER export in animal cells: adaptation and control for diverse cargo

“…This mode of action is inextricably linked to the formation of rings of TANGO1 at ERES (Liu et al 2017; Raote et al 2017). NBAS mutations in humans cause multisystem disorders (Segarra et al 2015) that do include defects in bone formation (Balasubramanian et al 2017) and can therefore be linked to impaired procollagen transport.…”

NBAS pathogenic variants: Defining the associated clinical and facial phenotype and genotype–phenotype correlations

“…NBAS‐associated facial phenotype and genotype–phenotype correlations. (a–d) Composite photos obtained from patients (Balasubramanian et al, ; Capo‐Chichi et al, ; Kortum et al, ; Maksimova et al, ; Megarbane et al, ; Regateiro et al, ; Staufner et al, ) and age‐/gender‐matched controls. Facial features of subjects with biallelic inactivating/hypomorphic NBAS variants include hypotelorism, thin upper lip, pointed chin, and a progeroid appearance.…”

“…So far, 47 different pathogenic NBAS variants have been reported in 71 individuals. To explore possible genotype–phenotype correlations, the available clinical data were collected (Table S5; Balasubramanian et al, ; Capo‐Chichi et al, ; Kortum et al, ; Maksimova et al, ; Megarbane et al, ; Regateiro et al, ; Segarra et al, ; Staufner et al, ; E‐P03.292008: European Society of Human Genetics 2018 meeting). A total of 36 patients have been reported to carry the homozygous p.Arg1914His change associated with the SOPH phenotype (Maksimova et al, ; Park & Lee, ), while two patients were reported to have a skeletal phenotype associated with the homozygous c.6237−3C>G splice‐site change (Palagano et al, ; Prontera et al, ).…”