Research Papers:

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

Hong-zhou Liu _, Chun-xian Du, Jing Luo, Xue-ping Qiu, Zu-hua Li, Qi-yong Lou, Zhan Yin and Fang Zheng

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Oncotarget. 2017; 8:2708-2718. https://doi.org/10.18632/oncotarget.13156

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Hong-zhou Liu1,*, Chun-xian Du2,*, Jing Luo1,*, Xue-ping Qiu1, Zu-hua Li1, Qi-yong Lou3, Zhan Yin3, Fang Zheng1

1Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China

2Department of Pneumology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China

3Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, Hubei, China

*These authors have contributed equally to this work

Correspondence to:

Fang Zheng, email: [email protected]

Keywords: pulmonary arteriovenous malformations, capillary malformations, nuclear prelamin A recognition factor-like, whole exome sequencing, zebrafish

Received: August 15, 2016    Accepted: October 12, 2016    Published: November 07, 2016


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.

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