PUBLICATION

A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations

Authors
Liu, H.Z., Du, C.X., Luo, J., Qiu, X.P., Li, Z.H., Lou, Q.Y., Yin, Z., Zheng, F.
ID
ZDB-PUB-161113-10
Date
2017
Source
Oncotarget   8(2): 2708-2718 (Journal)
Registered Authors
Yin, Zhan, Zheng, Fang
Keywords
capillary malformations, nuclear prelamin A recognition factor-like, pulmonary arteriovenous malformations, whole exome sequencing, zebrafish
MeSH Terms
  • Animals
  • Arteriovenous Malformations/diagnosis*
  • Arteriovenous Malformations/genetics*
  • Biopsy
  • Cell Line
  • Comparative Genomic Hybridization
  • Consanguinity
  • DNA Mutational Analysis
  • Female
  • Gene Knockdown Techniques
  • Genetic Association Studies*
  • Humans
  • Hydrogenase/chemistry
  • Hydrogenase/genetics*
  • Hydrogenase/metabolism
  • Immunohistochemistry
  • Models, Molecular
  • Mutation*
  • Neovascularization, Pathologic/genetics
  • Pedigree
  • Phenotype
  • Protein Conformation
  • Pulmonary Artery/abnormalities*
  • RNA Stability
  • Radiography, Thoracic
  • Tomography, X-Ray Computed
  • Whole Exome Sequencing
  • Young Adult
  • Zebrafish
PubMed
27835862 Full text @ Oncotarget
Abstract
Two daughters in a Chinese consanguineous family were diagnosed as diffuse pulmonary arteriovenous malformations (PAVMs) and screened using whole exome sequencing (WES) and copy number variations (CNVs) chips. Though no mutation was found in the established causative genes of capillary malformation-AVMs (CM-AVMs) or PAVMs, Ser161Ile (hg19 NM_022493 c.482G>T) mutation in nuclear prelamin A recognition factor-like (NARFL) was identified. Ser161Ile mutation in NARFL conservation region was predicted to be deleterious and absent in 500 population controls and Exome Aggregation Consortium (ExAC) Database. And there was a dosage effect of the mutation on mRNA levels among family members and population controls, consistent with the instability of mutant mRNA in vitro. Accordingly, in lung tissue of the proband, NARFL protein expression was reduced but Fe3+ was overloaded with vascular endothelial growth factor (VEGF) overexpression. Furthermore, NARFL-knockdown cell lines demonstrated decreased activity of cytosolic aconitase, while NARFL-knockout zebrafish presented ectopic subintestinal vessels sprouts and upregulated VEGF. So we concluded that the Ser161Ile mutant induced NARFL deficiency and eventually diffuse PAVMs probably through VEGF pathway. In a word, we detected a functional mutation in NARFL, which might be the pathogenic gene in this pedigree.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping