A novel mutation in nuclear prelamin a recognition factor-like causes diffuse pulmonary arteriovenous malformations.
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.
Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China.
Hong-Zhou
HZ
Liu
Department of Pneumology, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China.
Chun-Xian
CX
Du
Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China.
Jing
J
Luo
Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China.
Xue-Ping
XP
Qiu
Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China.
Zu-Hua
ZH
Li
Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, Hubei, China.
Qi-Yong
QY
Lou
Key Laboratory of Aquatic Biodiversity and Conservation of Chinese Academy of Sciences, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, Hubei, China.
Zhan
Z
Yin
Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430071, China.
Fang
F
Zheng
D000818:Animals; D001165:Arteriovenous Malformations / Q000175:diagnosis* / Q000235:genetics*; D001706:Biopsy; D002460:Cell Line; D055028:Comparative Genomic Hybridization; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D055785:Gene Knockdown Techniques; D056726:Genetic Association Studies; D006801:Humans; D006864:Hydrogenase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D007150:Immunohistochemistry; D007506:Iron-Sulfur Proteins; D008958:Models, Molecular; D009154:Mutation; D009389:Neovascularization, Pathologic / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D011487:Protein Conformation; D011651:Pulmonary Artery / Q000002:abnormalities*; D020871:RNA Stability; D013902:Radiography, Thoracic; D014057:Tomography, X-Ray Computed; D000073359:Exome Sequencing; D055815:Young Adult; D015027:Zebrafish
C516542:CIAO3 protein, human; D007506:Iron-Sulfur Proteins; D006864:Hydrogenase
capillary malformations; nuclear prelamin A recognition factor-like; pulmonary arteriovenous malformations; whole exome sequencing; zebrafish