This report describes neurodevelopmental disorder with hypotonia and speech delay, with or without seizures. The human gene implicated in this disease is EIF4A2, which encodes an ATP-dependent RNA helicase, and is involved in negative regulation of RNA-directed 5'-3' RNA polymerase activity. There is one high-scoring fly ortholog, Dmel\eIF4A, for which classical alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple UAS constructs of the human Hsap\EIF4A2, including wild-type EIF4A2 and variants implicated in disease, have been introduced into flies. See the 'Disease-Implicated Variants' table below. Variants characterized thus far are de novo missense variants.
Heterologous rescue (functional complementation) has been demonstrated: GMR-GAL4-driven RNAi knockdown of Dmel\eIF4A exhibits complete pupal lethality; this lethality can be rescued by expression of wild-type Hsap\EIF4A2. The tested variants failed or incompletely rescued the lethality.
[updated Apr. 2024 by FlyBase; FBrf0222196]
[NEURODEVELOPMENTAL DISORDER WITH HYPOTONIA AND SPEECH DELAY, WITH OR WITHOUT SEIZURES; NEDHSS](https://omim.org/entry/620455)
[EUKARYOTIC TRANSLATION INITIATION FACTOR 4A, ISOFORM 2; EIF4A2](https://omim.org/entry/601102)
Neurodevelopmental disorder with hypotonia and speech delay, with or without seizures (NEDHSS) is characterized by global developmental delay, impaired intellectual development with poor or absent speech, and fine and gross motor delay. Most affected individuals are severely affected and may be unable to walk, have feeding difficulties requiring tube-feeding, and develop early-onset seizures. Additional features may include cortical blindness and nonspecific structural brain abnormalities. Rare individuals present only with hypotonia and mild developmental delay (Paul, et al., 2023; pubmed:36528028; FBrf0255452). [from MIM:620455; 2023.08.23]
Autosomal dominant neurodevelopmental disorder with hypotonia and speech delay, with or without seizures (NEDHSS) is caused by heterozygous mutation in the EIF4A2 gene on chromosome 3q27. One family with compound heterozygous mutations has been reported. [from MIM:620455; 2023.08.23]
EIF4A2 encodes an ATP-dependent RNA helicase which is a subunit of the eIF4F complex involved in cap recognition and is required for mRNA binding to ribosome. In the current model of translation initiation, eIF4A unwinds RNA secondary structures in the 5'-UTR of mRNAs which is necessary to allow efficient binding of the small ribosomal subunit, and subsequent scanning for the initiator codon. [UniProtKB/Swiss-Prot Q14240]
Two to one (2 human to 1 Drosophila); EIF4A2 has one high-scoring Drosophila ortholog, eIF4A.
High-scoring ortholog of human EIF4A1 and EIF4A2 (1 Drosophila to 2 human).
