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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. Read the Editorial Highlight for this article on page 8. Cover Image for this issue: doi: 10.1111/jnc.14524.
Pubmed ID: 31318984
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Commercial antibody vendor which supplies antibodies and other products to life science researchers.
View all literature mentionsThis monoclonal targets PFKFB3
View all literature mentionsThis monoclonal targets HA Tag
View all literature mentionsThis monoclonal targets Cyclin B1
View all literature mentionsThis monoclonal targets GAPDH
View all literature mentionsThis monoclonal targets HA-Tag
View all literature mentionsThis monoclonal targets Rabbit n/a
View all literature mentionsThis unknown targets Goat Mouse IgG (H L)-HRP Conjugate
View all literature mentionsThis unknown targets Rabbit IgG (H+L)
View all literature mentionsThis monoclonal targets Cdh1
View all literature mentionsData analysis service to predict whether an amino acid substitution affects protein function based on sequence homology and the physical properties of amino acids. SIFT can be applied to naturally occurring nonsynonymous polymorphisms and laboratory-induced missense mutations. (entry from Genetic Analysis Software) Web service is also available.
View all literature mentionsA software tool which predicts whether an amino acid substitution or indel has an impact on the biological function of a protein.
View all literature mentionsOpen source Java based image processing software program designed for scientific multidimensional images. ImageJ has been transformed to ImageJ2 application to improve data engine to be sufficient to analyze modern datasets.
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsEvaluates disease-causing potential of sequence alterations.
View all literature mentionsSoftware package used for interactive, or batched, statistical analysis in social science, health sciences and marketing. Software platform offers advanced statistical analysis, a library of machine-learning algorithms, text analysis, open-source extensibility, integration with big data and deployment into applications.Versions that were produced by SPSS Inc. before the IBM acquisition (Versions 18 and earlier) would be given origin or publisher of SPSS Inc. in Chicago.
View all literature mentionsMus musculus with name C57BL/6J from IMSR.
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