This report describes hypotonia, ataxia, and delayed development syndrome (HADDS): HADDS exhibits autosomal dominant inheritance. The human gene implicated in this disease is EBF3, which encodes a member of the COE transcription factor family. There are three additional COE transcription factors in human, EBF1, EBR2, and EBF4. In Drosophila, there is a single orthologous gene, knot (kn), for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the human Hsap\EBF3 have been introduced into flies, including wild-type and variants implicated in HADDS. Using a GAL4 driver insertion within the endogenous Dmel\kn, appropriate tissue-specific expression is observed. Heterologous rescue (functional complementation) has been demonstrated: expression of the human gene rescues the lethal phenotype of homozygous amorphic mutations of Dmel\kn. The functional activity of the disease-implicated variants has been characterized by assessing whether these forms can rescue the kn lethal phenotype.
Variant(s) implicated in human disease tested (as transgenic human gene, EBF3): the R163Q and R163L variant forms have been introduced into flies. Neither variant is able to rescue the kn lethal phenotype.
Animals homozygous for amorphic mutations of Dmel\kn die in the embryonic stage. In late larval stages, homozygous somatic clones exhibit neuroanatomy defects. Physical and genetic interactions of Dmel\kn have been described; see below and in the kn gene report.
[updated Jan. 2018 by FlyBase; FBrf0222196]
[HYPOTONIA, ATAXIA, AND DELAYED DEVELOPMENT SYNDROME; HADDS](https://omim.org/entry/617330)
[EARLY B-CELL FACTOR 3; EBF3](https://omim.org/entry/607407)
HADDS is a neurodevelopmental syndrome characterized by congenital hypotonia, delayed psychomotor development, variable intellectual disability with speech delay, variable dysmorphic facial features, and ataxia, often associated with cerebellar hypoplasia. Some patients may have urogenital abnormalities (summary by Sleven et al., 2017; pubmed:28017370). [from MIM:617330; 2018.01.30]
Hypotonia, ataxia, and delayed development syndrome (HADDS) is caused by heterozygous mutation in the EBF3 gene. [from MIM:617330; 2018.01.30]
The EBF3 gene encodes a member of the highly conserved Collier/Olf/EBF (COE) family of transcription factors, which regulate neurogenesis and differentiation. [from MIM:607407; 2018.01.30]
Many to one: 4 human to 1 Drosophila; the human genes are EBF1, EBF2, EBF3, EBF4.
High-scoring ortholog of human EBF1, EBF2, EBF3, and EBF4 (1 Drosophila to 4 human). Dmel\kn shares 55-63% identity and 65-71% similarity with the human genes.
