Pathogenic mutations in the zinc finger C4H2-type gene (ZC4H2) are associated with a neurodevelopmental and neuromuscular disorder often diagnosed as a form of arthrogryposis multiplex congenita. ZC4H2 is a protein-coding gene located on the X-chromosome and the mechanism by which ZC4H2 mutations lead to disease remain unclear. Due to the key clinical features of both males and females with these mutations there is a growing recognition of this condition as a unique disorder that should be clinically recognized as ZARD.

The limited research published to date indicates that ZC4H2 is expressed at various developmental stages and is subject to X-inactivation in females. Inheritance of one ZC4H2 mutant allele (or de novo mutation) in males results in full expression of the disease, manifesting with severe impairment and developmental delays. Recent research has found that due to variation in X-inactivation or the presence of significant mutations in ZC4H2 (such as full deletions), females may also present with a form of the disease, albeit less severe than male ZC4H2 patients. It is believed that the pathogenic variants of ZC4H2 may result in impairment of the central and peripheral nervous system through the impairment of neurologic development.

ZC4H2 - Associated Rare Disorders (ZARD) Pilot Grant Program

Sought grant applications that progress the understanding of ZC4H2 basic biology or development of treatments and/or a cure for ZARD. Priority was given to grants that covered the following areas:

1. Unbiased approaches to discovering the protein function of ZC4H2, including, but not limited to, rescue, modifier, or synthetic lethal screens in genetically tractable model organisms.

2. Molecular characterization of ZC4H2 and the effect of mutations on molecular and protein function using in vitro and in in vivo models (mouse and human where possible):

   -identification and characterization of naturally occurring transcripts, including splice isoforms

   -spatio-temporal expression patterns of wildtype ZC4H2 expression at RNA and protein level (i.e. developmental time course and tissue- and cell type-specific expression of RNA and protein; cellular sub-localization of protein)

3. Discovery and validation of druggable targets or pathways for ZC4H2 treatment. Pilot data should be already established. This grant would focus on validating the approach in a translatable experiment with clear Go/ No Go experiments.

This grant opportunity is currently closed. Please check our Grant Page for open opportunities.

Awarded ZC4H2 Grants:

For an extensive list our JumpStart awarded grants, click here.