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
  • Arteriovenous Malformations/diagnosis*
  • Arteriovenous Malformations/genetics*
  • DNA Mutational Analysis
  • Protein Conformation
  • Young Adult
  • Models, Molecular
  • Biopsy
  • Pulmonary Artery/abnormalities*
  • Mutation*
  • Gene Knockdown Techniques
  • Consanguinity
  • Tomography, X-Ray Computed
  • Comparative Genomic Hybridization
  • Exome Sequencing
  • RNA Stability
  • Genetic Association Studies*
  • Zebrafish
  • Female
  • Animals
  • Neovascularization, Pathologic/genetics
  • Hydrogenase/chemistry
  • Hydrogenase/genetics*
  • Hydrogenase/metabolism
  • Immunohistochemistry
  • Radiography, Thoracic
  • Humans
  • Phenotype
  • Pedigree
  • Cell Line
(all 29)
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
Figure Gallery (1 images)
Show all Figures
Expression
Phenotype
Fish Conditions Stage Phenotype Figure
narflihb166/ihb166standard conditionsProtruding-mouth
narflihb166/ihb166standard conditionsProtruding-mouth
1 - 2 of 2
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ihb166
    		Indel
    1 - 1 of 1
    Show
    Human Disease / Model
    Human Disease Fish Conditions Evidence
    arteriovenous malformationTAS
    1 - 1 of 1
    Show
    Sequence Targeting Reagents
    Target Reagent Reagent Type
    narflCRISPR2-narflCRISPR
    1 - 1 of 1
    Show
    Fish
    Fish
    narflihb166/ihb166
    1 - 1 of 1
    Show
    Antibodies
    No data available
    Orthology
    No data available
    Engineered Foreign Genes
    No data available
    Mapping
    No data available
    Your Input Welcome
    We welcome your input and comments. Please use this form to recommend updates to the information in ZFIN. We appreciate as much detail as possible and references as appropriate. We will review your comments promptly.
    Citation
    Liu, H.Z., Du, C.X., Luo, J., Qiu, X.P., Li, Z.H., Lou, Q.Y., Yin, Z., Zheng, F. (2017) A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations. Oncotarget. 8(2):2708-2718.