Heterozygous loss-of-function DHX9 variants are associated with neurodevelopmental disorders: Human genetic and experimental evidences

Yamada, Mamiko; Nitta, Yohei; Uehara, Tomoko; Suzuki, Hisato; Miya, Fuyuki; Tamura, Toshiki; Tamura, Masahito; Ayabe, Shin-ichi; Yoshiki, Atsushi; Maeno, Akiteru; Saga, Yumiko; Furuse, Tamio; Yamada, Ikuko; Okamoto, Nobuhiko; Kosaki, Kenjiro; Sugie, Atsushi

doi:10.1016/j.ejmg.2023.104804

Cited by 14 publications

(4 citation statements)

References 27 publications

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“…We further investigated the pathogenic potential of a novel heterozygous de novo missense mutation in DHX9 in a patient presenting with short stature, intellectual disability, and myocardial compaction. Our findings indicated a loss of function in the G414R and R1052Q variants of DHX9 (Yamada et al, 2023). This experimental framework has been instrumental in elucidating the impact of gene mutations, enhancing our ability to diagnose how novel variants influence gene function.…”

Section: Discussionmentioning

confidence: 71%

Drosophilamodel to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy

Nitta

Osaka

Maki

et al. 2023

Preprint

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Autosomal dominant optic atrophy (DOA) is a progressive form of blindness caused by degeneration of retinal ganglion cells and their axons, mainly caused by mutations in the OPA1 mitochondrial dynamin like GTPase (OPA1) gene. OPA1 encodes a dynamin-like GTPase present in the mitochondrial inner membrane. When associated with OPA1 mutations, DOA can present not only ocular symptoms but also multi-organ symptoms (DOA plus). DOA plus often results from point mutations in the GTPase domain, which are assumed to have dominant negative effects. However, the presence of mutations in the GTPase domain does not always result in DOA plus. Therefore, an experimental system to distinguish between DOA and DOA plus is needed. In this study, we found that loss-of-function mutations of the dOPA1 gene in Drosophila can imitate the pathology of optic nerve degeneration observed in DOA. We successfully rescued this degeneration by expressing the human OPA1 (hOPA1) gene, indicating that hOPA1 is functionally interchangeable with dOPA1 in the fly system. However, we could not rescue any previously reported mutations known to cause either DOA or DOA plus. By expressing both WT and DOA plus mutant hOPA1 forms in the optic nerve of dOPA1 mutants, we observed that DOA plus mutations suppressed the rescue, facilitating the distinction between loss-of-function and dominant negative mutations in hOPA1. The fly model developed in this study can assist in the differential diagnosis between DOA and DOA plus and inform early treatment decisions in patients with mutations in hOPA1.

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Section: Discussionmentioning

confidence: 71%

Drosophilamodel to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy

Nitta

Osaka

Maki

et al. 2023

Preprint

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“…Informed consent for molecular genetic analysis was obtained from the patient, with approval from the local institutional review board. Exome analysis was performed as previously reported (10), revealing a heterozygous variant: ELN (OMIM # 123700) chr7:g.73477981delT (GRCh37), NM_001278939.1:c.2135del, p.(Leu712ProfsTer37), which was con rmed by Sanger sequencing (Figure .3). This variant was scored as "pathogenic" (PVS1, PM1, PM2, and PS6) according to the American College of Medical Genetics and Genomics standards and guidelines for the interpretation of sequence variants (11).…”

Section: Case Presentationmentioning

confidence: 78%

The first Japanese case of small airway disease in a patient with autosomal dominant cutis laxa harboring frameshift variant in exon 30 of the elastin gene

Kaji,

Namkoong,

Chubachi

et al. 2024

Preprint

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Background: Cutis laxa constitutes a diverse group of connective tissue diseases, both inherited and acquired, characterized by loose skin and varying systemic involvement, including pulmonary lesions. While cutis laxa has been linked to conditions like emphysema, asthma, and bronchiectasis, the specific pathological and radiological characteristics underlying pulmonary complications related to cutis laxa remain unclear. Case presentation: A 36-year-old woman, diagnosed with cutis laxa at birth, presented to our outpatient clinic with severe obstructive ventilatory impairment, evident in preoperative pulmonary function tests (expiratory volume in one second (FEV1)/forced vital capacity (FVC): 34.85%). Pulmonary function tests also indicated small airway disease (FEF50%, 7.9%; FEF75%, 5.7%; and FEF25–75%, 6.8%). Computed tomography (CT) revealed pronounced air trapping during expiration, with no discernible emphysematous changes. Exome sequencing was performed to confirm the association between the pulmonary lesions and cutis laxa, revealing a frameshift variant in exon 30 of the elastin gene (ELN). Further analysis employing a parametric response map revealed a longitudinal increase in the percentage of functional small airway disease (fSAD), despite the absence of overt changes in CT findings, specifically air trapping and emphysema. Conclusions: This case highlighted an instance of autosomal dominant cutis laxa arising from a frameshift variant in exon 30 of ELN, accompanied by small airway disease. Comprehensive investigation, utilizing quantitative CT analysis, revealed a longitudinal increase in fSAD percentage with a slight reduction in FEV1. These findings indicate that elastin deficiency may not only diminish elastic fibers in the skin but also be implicated in small airway disease by impacting components of the extracellular matrix in the lungs.

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“…Coinciding with GO analysis, Dhx9 knockout in the mouse causes embryonic lethality and Dhx9 knockdown leads to large structural changes in chromatin and eventually cell death (He et al, 2008;Zhang et al, 2004). Heterozygous loss-of-function variants of DHX9 are associated with neurodevelopmental disorders in human (Yamada et al, 2023).…”

Section: Modulation Of Co-localized G4s and R-loops By The Helicase Dhx9mentioning

confidence: 99%

Genome-wide mapping of native co-localized G4s and R-loops in living cells

Liu,

Shen,

Ren

et al. 2024

Preprint

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The non-B DNA structures can act as dynamic functional genomic elements regulating gene expression. Among them, G4s and R-loops are two of the best studied. The interplay between R-loops and G4s are emerging in regulating DNA repair, replication and transcription. A comprehensive picture of native co-localized G4s and R-loops in living cells is currently lacking. Here, we describe the development of HepG4-seq and an optimized HBD-seq methods, which robustly capture native G4s and R-loops, respectively, in living cells. We successfully employed these methods to establish comprehensive maps of native co-localized G4s and R-loops in human HEK293 cells and mouse embryonic stem cells (mESCs). We discovered that co-localized G4s and R-loops are dynamically altered in a cell type-dependent manner and are largely localized at active promoters and enhancers of transcriptional active genes. We further demonstrated the helicase Dhx9 as a direct and major regulator that modulates the formation and resolution of co-localized G4s and R-loops. Depletion of Dhx9 impaired the self-renewal and differentiation capacities of mESCs by altering the transcription of co-localized G4s and R-loops - associated genes. Taken together, our work established that the endogenous co-localized G4s and R-loops are prevalently persisted in the regulatory regions of active genes and are involved in the transcriptional regulation of their linked genes, opening the door for exploring broader roles of co-localized G4s and R-loops in development and disease.

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Heterozygous loss-of-function DHX9 variants are associated with neurodevelopmental disorders: Human genetic and experimental evidences

Cited by 14 publications

References 27 publications

Drosophilamodel to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy

Drosophilamodel to clarify the pathological significance of OPA1 in autosomal dominant optic atrophy

The first Japanese case of small airway disease in a patient with autosomal dominant cutis laxa harboring frameshift variant in exon 30 of the elastin gene

Genome-wide mapping of native co-localized G4s and R-loops in living cells

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