Yamada et al., 2023 demonstrated that two de novo missense variants in the DHX9 gene (a p.Arg1052Gln variant that was previously reported in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014, and a p.Gly414Arg variant that was identified in a novel patient presenting with developmental delay/intellectual disability, undergrowth, and ventricular non-compaction cardiomyopathy) resulted in aberrant localization and loss-of-function effects in transgenic Drosophila lines. In the same report, the authors also found that mice heterozygous for a p.Gly416Arg variant, which corresponded to the p.Gly414Arg variant, displayed reduced body weight, reduced emotionality, and cardiac conduction abnormalities (prolonged PR interval). Additional de novo variants in the DHX9 gene, including a de novo loss-of-function variant, have been identified in ASD probands from simplex families from the MSSNG cohort (Zhou et al., 2022), while a paternally-inherited DHX9 missense variant with a CADD score of 31 was identified in a Chinese ASD proband from the ACGC cohort (Guo et al., 2018). Calame et al., 2023 described 20 individuals with rare monoallelic DHX9 variants presenting with either a neurodevelopmental disorder characterized by developmental delay/intellectual disability, neuropsychiatric disorders (including autism spectrum disorder), seizures, axial hypotonia, and dysmorphic features, or Charcot-Marie-Tooth disease; subsequent functional studies demonstrated that DHX9 variants disrupted cellular localization and helicase activity and increased R-loops and double-stranded DNA breaks, while a Dhx9 -/- mice was shown to exhibit behavioral and neurological abnormalities in this report.
Molecular Function
This gene encodes a member of the DEAH-containing family of RNA helicases. The encoded protein is an enzyme that catalyzes the ATP-dependent unwinding of double-stranded RNA and DNA-RNA complexes. This protein localizes to both the nucleus and the cytoplasm and functions as a transcriptional regulator. This protein may also be involved in the expression and nuclear export of retroviral RNAs. Alternate splicing results in multiple transcript variants.
Variation in DHX genes, including DHX9, has been linked to neurodevelopmental disorders including autism spectrum disorder (ASD). The homozygous knockout model shows no change in viability but exhibits decreased body weight compared to sex-matched wildtypes. The model also shows altered behavioral and neurological function. Male and female model mice show decreased locomotion, with a decrease in distance traveled in the periphery of the open field and a decrease in locomotor speed. Additionally, model male and female mice demonstrate decreased grip strength, increased tremor, and decreased auditory functioning, as measured by the auditory brainstem response test. Furthermore, the model shows altered metabolic function, with possible altered renal function, decreased glucose clearance, and decreased cholesterol levels.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice were generated by allele conversion of the C57BL/6NCrl-Dhx9^Tm1a (EUCOMM) Hmgu mouse line. The tm1b allele (MGI:6472605) was produced by deletion of exon 4 of Dhx9 and the neomycin cassette by a cell-permeable Cre recombinase. The allele is a knockout given that skipping over of the LacZ cassette does not produce a functional protein. The cassette produces LacZ under the control of the Dhx9 promoter as a fusion protein with exon 3.
Allele Type: Knockout
Strain of Origin: C57BL/6N-A
Genetic Background: C57BL/6NCrl
ES Cell Line: JM8A1.N3
Mutant ES Cell Line: Model Source: Helmholtz Zentrum Muenchen GmbH
Description: 20% of Dhx9 mutant mice (3 of 15 mutants, 2 of 6 males, and 1 of 9 females) showed tremors in SHIRPA analysis, compared to 0% of wildtype controls.
Exp Paradigm: SHIRPA analysis
Description: Dhx9 mutant mice exhibited an increase in rearing activity during the active dark period of the light/dark cycle in a familiar home cage environment,
Exp Paradigm: dark period of the light/dark cycle
Description: Dhx9 mutant male and female mice exhibited a decrease in the distance traveled in the periphery of the open field and a decrease in locomotor speed.
Description: Dhx9 mutant male and female mice exhibited reduced food intake and more weight loss compared to wildtype controls in a 21 hour period after transfer to a new home cage.
Description: Dhx9 mutant male and female mice exhibited mild hypochromic microcytosis of erythrocytes, as indexed by increased red blood cell counts, decreased mean corpuscular volume (MCV), and decreased mean corpuscular hemoglobin (MCH). Moreover, lowered platelet counts in males were associated with higher mean platelet volumes and increased anisocytosis of platelets.
