PUBLICATION

Mutations in the Neuroblastoma Amplified Sequence gene in a family affected by Acrofrontofacionasal Dysostosis type 1

Authors
Palagano, E., Zuccarini, G., Prontera, P., Borgatti, R., Stangoni, G., Elisei, S., Mantero, S., Menale, C., Forlino, A., Uva, P., Oppo, M., Vezzoni, P., Villa, A., Merlo, G.R., Sobacchi, C.
ID
ZDB-PUB-180622-45
Date
2018
Source
Bone   114: 125-136 (Journal)
Registered Authors
Keywords
Development, Dysostosis, NBAS, Nonsense-mediated decay, Retrograde transport
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Female
  • HEK293 Cells
  • Humans
  • Infant
  • Male
  • Mandibulofacial Dysostosis/diagnostic imaging*
  • Mandibulofacial Dysostosis/genetics*
  • Mice
  • Mice, Inbred C57BL
  • Mutation/genetics*
  • Neoplasm Proteins/genetics*
  • Pregnancy
  • Siblings*
  • Zebrafish
PubMed
29929043 Full text @ Bone
Abstract
Acrofrontofacionasal Dysostosis type 1 (AFFND1) is an extremely rare, autosomal recessive syndrome, comprising facial and skeletal abnormalities, short stature and intellectual disability. We analyzed an Indian family with two affected siblings by exome sequencing and identified a novel homozygous truncating mutation in the Neuroblastoma-Amplified Sequence (NBAS) gene in the patients' genome. Mutations in the NBAS gene have recently been associated with different phenotypes mainly involving skeletal formation, liver and cognitive development. The NBAS protein has been implicated in two key cellular processes, namely the non-sense mediated decay and the Golgi-to-Endoplasmic Reticulum retrograde traffic. Both functions were impaired in HEK293T cells overexpressing the truncated NBAS protein, as assessed by Real-Time PCR, Western blot analysis, co-immunoprecipitation, and immunofluorescence analysis. We examined the expression of NBAS protein in mouse embryos at various developmental stages by immunohistochemistry, and detected expression in developing chondrogenic and osteogenic structures of the skeleton as well as in the cortex, hippocampus and cerebellum, which is compatible with a role in bone and brain development. Functional genetics in the zebrafish model showed that depletion of endogenous z-nbas in fish embryos results in defective morphogenesis of chondrogenic cranial skeletal elements. Overall, our data point to a conserved function of NBAS in skeletal morphogenesis during development, support the hypothesis of a causative role of the mutated NBAS gene in the pathogenesis of AFFND1 and extend the spectrum of phenotypes associated with defects in this gene.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping