Rabbit Anti-Human FZR1 (a.a. 141-240) Polyclonal antibody

The Fizzy-related protein 1 (Fzr1) gene encodes Cdh1 protein, a coactivator of the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C). Previously, we found that genetic ablation of Fzr1 promotes the death of neural progenitor cells leading to neurogenesis impairment and microcephaly in mouse. To ascertain the possible translation of these findings in humans, we searched for mutations in the Fzr1 gene in 390 whole exomes sequenced in trio in individuals showing neurodevelopmental disorders compatible with a genetic origin. We found a novel missense (p.Asp187Gly) Fzr1 gene mutation (c.560A>G) in a heterozygous state in a 4-year-old boy, born from non-consanguineous Spanish parents, who presents with severe antenatal microcephaly, psychomotor retardation, and refractory epilepsy. Cdh1 protein levels in leucocytes isolated from the patient were significantly lower than those found in his parents. Expression of the Asp187Gly mutant form of Cdh1 in human embryonic kidney 293T cells produced less Cdh1 protein and APC/C activity, resulting in altered cell cycle distribution when compared with cells expressing wild-type Cdh1. Furthermore, ectopic expression of the Asp187Gly mutant form of Cdh1 in cortical progenitor cells in primary culture failed to abolish the enlargement of the replicative phase caused by knockout of endogenous Cdh1. These results indicate that the loss of function of APC/C-Cdh1 caused by Cdh1 Asp187Gly mutation is a new cause of prenatal microcephaly, psychomotor retardation, and severe epilepsy. Open science badges This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at . Open Science: This manuscript was awarded with the Open Materials Badge For more information see:

Nickel (II) is a ubiquitous environmental contaminant and it is known to be a highly toxic metal. The level of nickel in the environment has been raised with advances in industrialization and the role of nickel in human diseases is of increasing concern. Thioredoxin reductase 1 (Trr 1) is one of major redox factors having a potential role in cellular defense system against exposure to environmental toxicants. In this study, we investigated the protective roles of the Trr 1 against nickel-induced DNA damage. We found significantly higher amounts of DNA strand break in Trr 1 silencing cells compared to Trr 1 wild-type cells under nickel exposure, using gamma-H2AX immunofluorescence staining. We also identified the potential molecular biomarkers that participated in gene-environment interaction between Trr 1 deficiency and nickel exposure via microarray analysis. In particular, seven upregulated genes (AHNAK, FZR1, LGALS7, PLD1, PPM1F, RHOB and SFRP1) and three down-regulated genes (IFITM1, MAPK8 and RCN1), whose functions are principally in toxicity-prone as well as cytoprotection processes, including cell proliferation, cell survival, apoptosis, inflammation and DNA repair. Our findings demonstrate gene-environment interaction between Trr 1 deficiency and nickel-induced toxicity, as evidence that insufficient of redox factor Trr 1 accelerated DNA lesions caused by nickel exposure. These results suggest that the candidate genes might be further useful in the establishment of Trr 1-mediated strategies by which modulate cellular defense against environmental toxicants, nickel.