The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants

Homma, Kazuaki

doi:10.3390/biomedicines10092254

Cited by 9 publications

(7 citation statements)

References 124 publications

(94 reference statements)

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“…40,41 The last group of genes that showed nominally significant relationship with speech and or language phenotypes were known to be contributory to hearing loss: GJB2 and KCNQ1 . 42,43 The breadth of the genetic diagnoses spectrum illustrates the various dimensions of potential aetiologies of speech impairment, ranging from epileptic encephalopathies to movement disorders and hearing loss, mirroring the findings of our phenotypic-based analysis. Disentangling speech and language phenotype-genotype association warrants further examination; we identified several relationships, but no genes that would be explanatory for speech and language impairments alone were identified in our cohort.…”

Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 57%

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The clinical and genetic spectrum of paediatric speech and language disorders in 52,143 individuals

Magielski,

Ruggiero,

Xian

et al. 2024

Preprint

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Speech and language disorders are known to have a substantial genetic contribution. Although frequently examined as components of other conditions, research on the genetic basis of linguistic differences as separate phenotypic subgroups has been limited so far. Here, we performed an in-depth characterization of speech and language disorders in 52,143 individuals, reconstructing clinical histories using a large-scale data mining approach of the Electronic Medical Records (EMR) from an entire large paediatric healthcare network. The reported frequency of these disorders was the highest between 2 and 5 years old and spanned a spectrum of twenty-six broad speech and language diagnoses. We used Natural Language Processing to assess to which degree clinical diagnosis in full-text notes were reflected in ICD-10 diagnosis codes. We found that aphasia and speech apraxia could be easily retrieved through ICD-10 diagnosis codes, while stuttering as a speech phenotype was only coded in 12% of individuals through appropriate ICD-10 codes. We found significant comorbidity of speech and language disorders in neurodevelopmental conditions (30.31%) and to a lesser degree with epilepsies (6.07%) and movement disorders (2.05%). The most common genetic disorders retrievable in our EMR analysis wereSTXBP1(n=21),PTEN(n=20), andCACNA1A(n=18). When assessing associations of genetic diagnoses with specific linguistic phenotypes, we observed associations ofSTXBP1and aphasia (P=8.57 x 10-7, CI=18.62-130.39) andMYO7Awith speech and language development delay due to hearing loss (P=1.24 x 10-5, CI=17.46-Inf). Finally, in a sub-cohort of 726 individuals with whole exome sequencing data, we identified an enrichment of rare variants in synaptic protein and neuronal receptor pathways and associations ofUQCRC1with expressive aphasia andWASHC4with abnormality of speech or vocalization. In summary, our study outlines the landscape of paediatric speech and language disorders, confirming the phenotypic complexity of linguistic traits and novel genotype-phenotype associations. Subgroups of paediatric speech and language disorders differ significantly with respect to the composition of monogenic aetiologies.

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Section: Discussionsupporting

confidence: 53%

Section: Discussionmentioning

confidence: 57%

The clinical and genetic spectrum of paediatric speech and language disorders in 52,143 individuals

Magielski,

Ruggiero,

Xian

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“… 29 , 30 The genetic mutations of KCNQ1 gene have been reported to be related to type 2 diabetes, 31 cardiovascular diseases 32 and deafness. 33 , 34 Thus far, only a GWAS research of Han Chinese found a correlation of KCNQ1 variants with gout while not hyperuricemia, 14 which mechanisms supposed be responsible of immune regulation. The amplification of inflammation of KCNQ1 blocker intervention in our gout mouse model was consistent with the hypothesis that KCNQ1 mediates gouty inflammation.…”

Section: Discussionmentioning

confidence: 99%

Suppression of P2X7R by Local Treatment Alleviates Acute Gouty Inflammation

Zhao,

Li,

Chen

et al. 2023

JIR

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Objective Gout is the most common inflammatory arthritis associated with interleukin-1β (IL-1β) accumulation during exacerbation. In this study, we aimed to clarify whether potassium channel antagonists attenuate local inflammation in mice with monosodium urate (MSU)-induced gout. Methods We cultured human macrophage THP-1 cells and evaluated the molecular levels of both IL-1β and potassium channels stimulated with MSU and/or potassium channel antagonists. Acute gout models were generated in IL-1β luciferase transgenic male mice using synovium-like subcutaneous air pouches with MSU injection. Their luciferase activities were monitored following potassium channel blocker treatment using the IVIS Spectrum CT imaging system. The lavages and tissues were extracted from their air pouches, followed by cell counting and pathological analysis. Results MSU stimulation increased the gene expression levels of pro-IL-1β, P2x7r and Kv1.3 , whereas the expression of Kcnq1 was decreased in phorbol 12-myristate 13-acetate-induced THP-1 cells. Both high and low concentrations of the P2x7 receptor inhibitor adenosine 5′-triphosphate (ATP) derivative periodate oxidized ATP (oATP) decreased the production of IL-1β in the supernatant of THP-1 cells. The sixth hour was the peak time of IL-1β luciferase activity after MSU intervention in vivo. oATP ameliorated the synovial IL-1β luciferase activity, reduced inflammatory cell infiltration and alleviated the erosive damage in the cartilage. Conclusion The anti-inflammatory properties of potassium channel inhibitors, especially of oATP, might point to new strategies for local anti-inflammatory therapy for acute gout.

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“…This study KCNQ4 was explored the expression and prognosis of in human malignant tumors. Many studies have shown that KCNQ4 is a member of voltage-gated potassium channel, and the decrease of KCNQ4 activity caused by gene mutation is the cause of non-syndromic hearing loss [32] . In the nervous system, the KCNQ4 subunit is present in a subpopulation of cholinergic neurons in the peduncular pontine nucleus, suggesting that it contributes to the regulation of the sleep-wake cycle [33] .…”

Section: Page 9/27mentioning

confidence: 99%

Comprehensive pan‑cancer analysis of Potassium Voltage-Gated Channel Q4 (KCNQ4 ) gene expression in human malignant tumors

Zhao

Zhang

2023

Preprint

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Background: Malignant tumor is a serious threat to human health and has become the disease with the highest mortality in the world. A large number of studies have shown that KCNQ4 is responsible for nonsyndromic hearing loss, but less has been done on KCNQ4 in cancer, so we analyzed the expression of KCNQ4 gene in different tumor tissues and their different pathological stages, the prognosis, mutation, immune infiltration, immune checkpoint related genes and related pathways were observed. The role and function of KCNQ4 in cancer were revealed through systematic and comprehensive pan-cancer analysis. Method: The bioinformatics were analyzed by mining databases available to the public and by using R software. Moreover, immunohistochemistry and molecular biology experiments were carried out to prove the cancer-inhibiting effect of KCNQ4 in pan-cancer. Results: The results showed that KCNQ4 expression was lower than normal tissues in most tumors,and higher in a few tumors. The expression of KCNQ4 gene was closely related to the prognosis of patients with different types of tumors. The expression of KCNQ4 was significantly correlated with different pathological stages in papillary renal cell carcinoma, mixed renal cell carcinoma, hepatocellular carcinoma, rectal adenocarcinoma, pancreatic carcinoma, ovarian serous cystadenocarcinoma and bladder urothelial carcinoma. The mutation rate of KCNQ4 was the highest in patients with cutaneous melanoma.KCNQ4 is significantly associated with immune infiltration and immune checkpoint related genes in most tumors.KCNQ4,stemness analysis shows a positive correlation in most cancer species. KCNQ4 and related genes were significantly enriched in multiple pathways. Moreover, immunohistochemical and molecular biological experiments verified that KCNQ4 has less expression in breast cancer tissues and has anti-tumor effect in breast cancer. Discussion: Our comprehensive pan-cancer analysis of KCNQ4 proved its potential signature role in cancer，Moreover，KCNQ4 could be used as an auxiliary prognostic marker or as a marker for immunotherapy in some tumor types.

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The Pathological Mechanisms of Hearing Loss Caused by KCNQ1 and KCNQ4 Variants

Cited by 9 publications

References 124 publications

The clinical and genetic spectrum of paediatric speech and language disorders in 52,143 individuals

The clinical and genetic spectrum of paediatric speech and language disorders in 52,143 individuals

Suppression of P2X7R by Local Treatment Alleviates Acute Gouty Inflammation

Comprehensive pan‑cancer analysis of Potassium Voltage-Gated Channel Q4 (KCNQ4 ) gene expression in human malignant tumors

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