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Bone. 2017 Jan;94:65-74. doi: 10.1016/j.bone.2016.10.023. Epub 2016 Oct 24.

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

Author information

1
Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, UK; Highly Specialised Service for Severe, Complex and Atypical OI, UK. Electronic address: meena.balasubramanian@nhs.net.
2
NE Thames Clinical Genetics Service, Great Ormond Street Hospital, UK.
3
Sheffield RNAi Screening Facility, Department of Biomedical Sciences, University of Sheffield, UK.
4
Highly Specialised Service for Severe, Complex and Atypical OI, UK; Academic Unit of Child Health, University of Sheffield, UK.
5
Highly Specialised Service for Severe, Complex and Atypical OI, UK.
6
Academic Unit of Child Health, University of Sheffield, UK; Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, UK.
7
Sheffield Diagnostic Genetics Service, Sheffield Children's NHS Foundation Trust, UK; Department of Biosciences and Chemistry, Sheffield Hallam University, UK.
8
MRC Human Genetics Unit, IGMM, University of Edinburgh, UK.
9
Department of Paediatric Immunology, Sheffield Children's NHS Foundation Trust, UK.
10
Department of Paediatric Hepatology, Sheffield Children's NHS Foundation Trust, UK.
11
Department of Paediatric Haematology, Sheffield Children's NHS Foundation Trust, UK.
12
Department of Histopathology, Sheffield Teaching Hospitals NHS Foundation Trust, UK.
13
DDD Study, Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
14
Sheffield Clinical Genetics Service, Sheffield Children's NHS Foundation Trust, UK.
15
Centre for Computational Biology, Sheffield Institute of Translational Neuroscience, University of Sheffield, UK.
16
Mellanby Bone Research Centre, Department of Oncology & Metabolism, University of Sheffield, UK.

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.(Gln678*) 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.

KEYWORDS:

Bone; Collagen expression; Fragility; NBAS; Nonsense mediated decay (NMD); Osteogenesis imperfecta; Secretory pathway

PMID:
27789416
PMCID:
PMC6067660
DOI:
10.1016/j.bone.2016.10.023
[Indexed for MEDLINE]
Free PMC Article

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