Background: Autosomal recessive disorder is closely correlated with congenital fetal malformation. The mutation of WDR35 may lead to short rib-polydactyly syndrome (SRP), asphyxiating thoracic dystrophy (ATD, Jeune syndrome) and Ellis van Creveld syndrome. The purpose of this study is to investigate the role of WDR35 in fetal anomaly.
Results: The fetuses presented malformation with abnormal head shape, cardiac dilatation, pericardial effusion, and non-displayed left pulmonary artery and left lung. After the detection of genomic DNA (gDNA) in amniotic fluid cells (AFC), chromosomal rearrangement was found in arr[hg19] 2p25.3p23.3. It was revealed through multiple PCR-DHPLC that MYCN, WDR35, LPIN1, ODC1, KLF11 and NBAS contained duplicated copy numbers in 2p25.3p23.3. AF-MSCs were mostly positive for CD44, CD105, negative for CD34 and CD14. Western Blot test showed that WDR35-encoded protein was decreased in the patients' AFC compared to that in normal pregnant women. In the patients' amniotic fluid-derived mesenchymal stem cells (AF-MSCs), WDR35 overexpression could repair cilia formation, and the overexpression of WDR35 or Gli2 could significantly enhance ALP activity and expressions of osteogenic differentiation marker genes, including RUNXE2, OCN, BSP and ALP. However, WDR35 silencing in C3H10T1/2 cells could remarkably inhibit cilia formation and osteogenic differentiation. This inhibitory effect could be attenuated by Gli2 overexpression.
Conclusions: The results demonstrated that copy number variation (CNV) of WDR35 may lead to skeletal dysplasia and fetal anomaly, and that down-regulated WDR35 may damage the cilia formation and sequentially indirectly regulate Gli signal, which would eventually result in negative regulation of osteogenic differentiation.
Keywords: Cilia formation; Fetal malformation; Gli2; Osteogenic differentiation; WDR35.
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