A dominant variant in DMXL2 is linked to nonsyndromic hearing loss

Chen, Dongye; Liu, Xing-Feng; Lin, Xiaojiang; Zhang, Dan; Chai, Yimin; Yu, Dehong; Sun, Changling; Wang, Xueling; Zhu, Weidong; Chen, Ying; Sun, Liang; Wang, Xiaowen; Shi, Fei; Huang, Zhiwu; Yang, Tao; Wu, Hao

doi:10.1038/gim.2016.142

Cited by 29 publications

(35 citation statements)

References 10 publications

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“…1) are reported to have no major learning difficulties, diagnosed psychiatric conditions, or features of a NDD. There is no known history of unexplained hearing loss in the family [41] nor of infertility or recurrent (> 2) miscarriage, delayed puberty, hypothyroidism, peripheral neuropathy, or short stature [42]. Facial photographs of the proband and her two daughters are available upon request; there are no notable dysmorphic features.…”

Section: Resultsmentioning

confidence: 99%

Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders

Costain

Walker

Argiropoulos

et al. 2019

J Neurodevelop Disord

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BackgroundUltra-rare genetic variants, including non-recurrent copy number variations (CNVs) affecting important dosage-sensitive genes, are important contributors to the etiology of neurodevelopmental disorders (NDDs). Pairing family-based whole-genome sequencing (WGS) with detailed phenotype data can enable novel gene associations in NDDs.MethodsWe performed WGS of six members from a three-generation family, where three individuals each had a spectrum of features suggestive of a NDD. CNVs and sequence-level variants were identified and further investigated in disease and control databases.ResultsWe identified a novel 252-kb deletion at 15q21 that overlaps the synaptic gene DMXL2 and the gene GLDN. The microdeletion segregated in NDD-affected individuals. Additional rare inherited and de novo sequence-level variants were found that may also be involved, including a missense change in GRIK5. Multiple CNVs and loss-of-function sequence variants affecting DMXL2 were discovered in additional unrelated individuals with a range of NDDs.ConclusionsDisruption of DMXL2 may predispose to NDDs including autism spectrum disorder. The robust interpretation of private variants requires a multifaceted approach that incorporates multigenerational pedigrees and genome-wide and population-scale data.

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Section: Resultsmentioning

confidence: 99%

Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders

Costain

Walker

Argiropoulos

et al. 2019

J Neurodevelop Disord

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“…Interestingly, the 34 mRNAs included all 29 mRNAs enriched in GO: 0007605. These 34 mRNAs included the genes that participated in the shaping of the hair bundle, such as Usher syndrome type 1C (Ush1c), Myo7a, protocadherin 15 (Pcdh15) [27], Eps8-related protein 2 (Eps8l2) [28] protein-tyrosine phosphatase, receptor-type, q (Ptprq) [29] and cadherin 23 (Cdh23) [30]; the genes associated with hair cell function, such as Pou domain, class 4, transfection factor 3 (Pou4f3) [31,32], potassium channel, voltage-gated, kqt-like subfamily, member 4 (Kcnq4) [33,34], diaphanous-related formin 1 (Diaph1) [35]and lipoxygenase homology domain-containing 1 (Loxhd1) [36]; the genes related to hair cell stereocilia, such as myosin XVA (Myo15a) [37] and family with sequence similarity 65, member b (Fam65b) [38]; the genes involved in the tectorial membrane, such as carcinoembryonic antigen-related cell adhesion molecule 16 (Ceacam16) [39] and tectorin alpha (Tecta) [40]; and other genes essential for inner ear development and function, such as Hgf [41], direct iap-binding protein with low pi (Diablo) [42], estrogen-related receptor beta (Esrrb) [43], otoancorin (Otoa) [44], otogelin-like protein (Otogl) [45] and dmx-like 2 (Dmxl2) [46]. These results suggest that the differentially expressed lncRNAs identified by this study most likely play roles in AHL by regulating the expression of the above mentioned genes.…”

Section: Discussionmentioning

confidence: 99%

RNA-seq analysis of potential lncRNAs for age-related hearing loss in a mouse model

Zhao

Liu

Sun

et al. 2020

Aging

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Age-related hearing loss (AHL) is an important health problem in the elderly population. Its molecular mechanisms have not been fully elucidated. In this study, we analyzed the differential expression of lncRNAs and mRNAs in the cochleae of six-week-old and one-year-old C57BL/6J mice through RNA-seq analysis. We found 738 and 2033 differentially expressed lncRNAs and mRNAs, respectively, in these two groups (corrected P < 0.05). We focused on the intersection of known genes associated with hearing loss and differentially expressed mRNAs in RNA-seq. There are 34 mRNAs in this intersection, which include all 29 mRNAs enriched in the sensory perception of sound (GO: 0007605). We selected 11 lncRNAs that are predicted to regulate the 34 mRNAs to validate their expression levels in animal and cellular models of AHL by qRT-PCR. Among these lncRNAs, four were significantly different in both animal and cellular models of AHL, and the lncRNA NONMMUT010961.2 was the most markedly different. Knocking down lncRNA NONMMUT010961.2, we found the expression of oxidative stress and apoptosis-related gene Ar and hearing loss-related gene Hgf is significantly reduced in HEI-OC1 cells. Our results suggest that lncRNAs NONMMUT010961.2 may be associated with AHL and may thus lead to a new treatment for AHL.

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“…DMXL2+/− mice show differences in corpus callosum neuroanatomy compared to wild type animals [25]. Along these lines, Chen and co-workers [33] linked an RB-3α missense variant to nonsyndromic hearing loss. Altogether, this strongly suggests that RB-3α is a key regulator in neuronal and homeostatic processes.…”

Section: Resultsmentioning

confidence: 99%

Interactions of Rabconnectin-3 with Cav2 calcium channels

et al. 2019

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This study describes the interaction between Cav2 calcium channels and Rabconnectin-3, a di-subunit protein that is associated with synaptic vesicles. Immunostaining reveals that both Rabconnectin-3α (RB-3α) and Rabconnectin-3β (RB-3β) are colocalized in mouse hippocampal neurons. Co-immunoprecipitations from brain tissue is consistent with the formation of a protein complex between RB-3α and RB-3β and both Cav2.2 and the related Cav2.1 calcium channel. The coexpression of either RB-3α or RB-3β with Cav2.2 calcium channels in tsA-201 cells led to a reduction in Cav2.2 current density without any effects on the voltage-dependence of activation or inactivation. Coexpression of both Rabconnectin-3 subunits did not cause an additive effect on current densities. Finally, the presence of Rabconnectin-3 did not interfere with μ-opioid receptor mediated Gβγ modulation of Cav2.2 channels. Altogether, our findings show that Rabconnectin-3 has the propensity to regulate calcium entry mediated by Cav2.2 channels.

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A dominant variant in DMXL2 is linked to nonsyndromic hearing loss

Abstract: Our data indicated that the p.Arg2417His variant in DMXL2 is associated with dominant, nonsyndromic hearing loss and suggested an important role of DMXL2 in inner ear function.Genet Med advance online publication 22 September 2016.

Cited by 29 publications

References 10 publications

Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders

Rare copy number variations affecting the synaptic gene DMXL2 in neurodevelopmental disorders

RNA-seq analysis of potential lncRNAs for age-related hearing loss in a mouse model

Interactions of Rabconnectin-3 with Cav2 calcium channels

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