• neurodevelopmental disorder with eye movement abnormalities and ataxia

This report describes neurodevelopmental disorder with eye movement abnormalities and ataxia (NEDEMA), a newly identified disorder also characterized by developmental delay, intellectual disability, and seizures; NEDEMA exhibits autosomal dominant inheritance. The human gene implicated in this disorder is FRMD5, which encodes a protein that enables integrin binding activity and may be involved in regulation of cell adhesion and cell migration. There is a single orthologous gene in Drosophila, Frmd5, for which a small number of genetic reagents has been generated, including a tagged loss-of-function mutation and RNAi-targeting constructs. Dmel\Frmd5 is also orthologous to human FRMD3.

Drosophila Frmd5 is expressed in glial cells of central nervous system. Animals carrying a loss-of-function mutation survive to adulthood, but are extremely sensitive to heat shock, which induces severe seizures, and exhibit defective responses to light.

Multiple UAS constructs of the human Hsap\FRMD5 gene, including wild-type and variants implicated in disease, have been introduced into flies. Variants characterized thus far appear to have occurred de novo; all act as loss of function variants. See the 'Disease-Implicated Variants' table, below. Heterologous rescue (functional complementation) has been demonstrated for loss-of-function phenotypes of Drosophila Frmd5. Loss-of-function variants of Hsap\FRMD5 fail to rescue, or fail to rescue completely, the Frmd5 phenotypes. Overexpression of Hsap\FRMD5 is toxic in a dose-dependent manner; ubiquitous expression results in lethality or semi-lethality. Ubiquitous expression of the characterized variants is less toxic.

[updated Nov. 2022 by FlyBase; FBrf0222196]