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

Area of Science:

• Genetics
• Vascular Biology
• Biochemistry

Background:

• Diffuse pulmonary arteriovenous malformations (PAVMs) are rare vascular anomalies.
• The genetic basis of many PAVMs remains largely unknown, necessitating further research into causative genes.

Purpose of the Study:

• To identify the genetic cause of diffuse PAVMs in a Chinese consanguineous family.
• To investigate the functional impact of a novel mutation in the nuclear prelamin A recognition factor-like (NARFL) gene on PAVM development.

Main Methods:

• Whole exome sequencing (WES) and copy number variation (CNV) analysis were performed on affected family members.
• Functional studies included in vitro mRNA stability assays, protein expression analysis, and NARFL knockdown/knockout in cell lines and zebrafish models.
• Bioinformatic predictions assessed the deleteriousness of the identified mutation.

Main Results:

• A novel Ser161Ile mutation in the NARFL gene was identified in affected individuals, absent in population controls.
• The NARFL mutation led to reduced protein expression, decreased cytosolic aconitase activity, and iron overload (Fe3+).
• NARFL deficiency was associated with vascular endothelial growth factor (VEGF) overexpression and ectopic vessel formation in zebrafish.

Conclusions:

• The identified NARFL Ser161Ile mutation is likely the pathogenic cause of diffuse PAVMs in this family.
• NARFL deficiency, potentially through the VEGF pathway, contributes to the pathogenesis of diffuse PAVMs.
• This study highlights NARFL as a potential novel gene associated with PAVMs.