Hypotonia, Ataxia, and Delayed Development syndrome (HADDS) is caused by heterozygous loss of EBF3 function (Chao et al. 2017; Harms et al. 2017; Sleven et al. 2017). The main clinical features of this multi-systemic disorder encompass a variety of symptoms like mild to moderate intellectual disability, developmental delay, ataxia, autism and autistic-like behaviors, distinct facial features, and congenital urogenital abnormalities. Currently no targeted therapy is available and only supportive are can be provided for symptom management. Therefore, elucidating the pathophysiological mechanisms underlying the cognitive deficits is essential for facilitating the development of targeted therapies.
EBF3 is a member of the Collier/Olf/EBF (COE) family of transcription factors noteworthy for their regulation of inhibitory g-aminobutyric acid (GABA) interneuron development (Wang et al. 2004; Wang et al. 1997). Loss of function manipulations in well-conserved homologs in worms, flies, frogs, and mice have consistently shown to impair survival (Crozatier et al. 1996; Pozzoli et al. 2001; Prasad et al. 1998; Wang et al. 2004). Mouse Ebf3 in the developing nervous system is expressed in the epithalamus, cerebellum, mesencephalon ventricular zone, ventral surface of the rhombencephalon, and spinal cord (Wang et al. 2004).
Heterozygous EBF3 gene variants impair EBF3-mediated transcriptional activation and result in a syndromic disorder characterized by intellectual disability, developmental delay, ataxia, expressive language impairment, and motor stereotypies (Harms et al. 2017; Sleven et al. 2017). All of the reported variants cluster predominantly in the DNA binding domain with enrichment around an atypical zinc finger (COE motif) critical for binding to DNA and were shown to impair transcriptional activation (Chao et al. 2017; Harms et al. 2017; Sleven et al. 2017).
To study the consequences of the human variants in vivo, we capitalized on the strong evolutionary conservation of COE transcription factors between invertebrates and vertebrates. The fruit fly has only one COE transcription factor, knot (kn), and complete loss of kn results in embryonic lethality (Liberg et al. 2002). We utilized the UAS-GAL4 system with a kn-t2A-GAL4 allele in conjunction with UAS-human cDNA lines and determined the EBF3 variants were damaging in vivo (Chao et al. 2017). Now we are examining the molecular and cellular mechanisms underlying the neurodevelopmental perturbations resulting from loss of EBF3 function, and elucidating the longitudinal clinical findings in EBF3-related HADDS.
Researchers in Houston, TX have a longitudinal natural history study for EBF3-related HADDS and is recruiting interested participants.