A novel pathogenic variant c.975G&gt;A (p.Trp325*) in the POU3F4 gene in Yakut family (Eastern Siberia, Russia) with the X-linked deafness-2 (DFNX2)

Barashkov, Nikolay A.; Klarov, Leonid A.; Teryutin, Fedor M.; Solovyev, Alexey V.; Pshennikova, Vera G.; Konnikova, E.E.; Romanov, Georgii P.; Тобохов, А. В.; Морозов, И. В.; Bondar, Alexander A.; Posukh, Olga L.; Dzhemileva, Lilya U.; Tomsky, Mikhail I.; Khusnutdinova, Elza; Fedorova, Sardana A.

doi:10.1016/j.ijporl.2017.11.001

Cited by 8 publications

(16 citation statements)

References 33 publications

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“…Samples were prepared using ultra rapid multiplex PCR technology combined with subsequent sequencing (AmpliSeq™). The genes that were included in this panel were selected according to the prevalence reported and the results of exome sequencing of Russian patients [ 10 , 32 , 33 , 34 , 35 ]. In this case, 29 genes included in the panel are the most common causes of NSHL according to world data.…”

Section: Methodsmentioning

confidence: 99%

Spectrum of Genes for Non-GJB2-Related Non-Syndromic Hearing Loss in the Russian Population Revealed by a Targeted Deafness Gene Panel

Shatokhina

Галеева

Степанова

et al. 2022

IJMS

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Hearing loss is one of the most genetically heterogeneous disorders known. Over 120 genes are reportedly associated with non-syndromic hearing loss (NSHL). To date, in Russia, there have been relatively few studies that apply massive parallel sequencing (MPS) methods to elucidate the genetic factors underlying non-GJB2-related hearing loss cases. The current study is intended to provide an understanding of the mutation spectrum in non-GJB2-related hearing loss in a cohort of Russian sensorineural NSHL patients and establish the best diagnostic algorithm. Genetic testing using an MPS panel, which included 33 NSHL and syndromic hearing loss (SHL) genes that might be misdiagnosed as NSHL genes, was completed on 226 sequentially accrued and unrelated patients. As a result, the molecular basis of deafness was found in 21% of the non-GJB2 NSHL cases. The total contribution pathogenic, and likely pathogenic, variants in the genes studied among all hereditary NSHL Russian patients was 12%. STRC pathogenic and likely pathogenic, variants accounted for 30% of diagnoses in GJB2-negative patients, providing the most common diagnosis. The majority of causative mutations in STRC involved large copy number variants (CNVs) (80%). Among the point mutations, the most common were c.11864G>A (p.Trp3955*) in the USH2A gene, c.2171_2174delTTTG (p.Val724Glyfs*6) in the STRC gene, and c.107A>C (p.His36Pro) and c.1001G>T (p.Gly334Val) in the SLC26A4 gene. Pathogenic variants in genes involved in SHL accounted for almost half of the cases with an established molecular genetic diagnosis, which were 10% of the total cohort of patients with non-GJB2-related hearing loss.

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Section: Methodsmentioning

confidence: 99%

Spectrum of Genes for Non-GJB2-Related Non-Syndromic Hearing Loss in the Russian Population Revealed by a Targeted Deafness Gene Panel

Shatokhina

Галеева

Степанова

et al. 2022

IJMS

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“…According to a fairly recent study, the severity of vestibular dysfunction associated with hearing loss is a determinant of comorbid hyperactivity or anxiety 74 . Vestibular symptoms are common in DFNX2 patients 8,42,47,75,76 . They have been associated with delayed developmental motor milestones, hypotonia and incoordination in early childhood, 27,38,39,42,47,52,65,66 and with dystaxia and postural disorders later in life 8,76 …”

Section: Pou3f4 ‐Related Hearing Loss Is Associated With Neurodevelop...mentioning

confidence: 99%

Considering gene therapy to protect from X‐linked deafness DFNX2 and associated neurodevelopmental disorders

Defourny

2022

Ibrain

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Mutations and deletions in the gene or upstream of the gene encoding the POU3F4 transcription factor cause X-linked progressive deafness DFNX2 and additional neurodevelopmental disorders in humans. Hearing loss can be purely sensorineural or mixed, that is, with both conductive and sensorineural components. Affected males show anatomical abnormalities of the inner ear, which are jointly defined as incomplete partition type III. Current approaches to improve hearing and speech skills of DFNX2 patients do not seem to be fully effective. Owing to inner ear malformations, cochlear implantation is surgically difficult and may predispose towards severe complications. Even in cases where implantation is safely performed, hearing and speech outcomes remain highly variable among patients. Mouse models for DFNX2 deafness revealed that sensorineural loss could arise from a dysfunction of spiral ligament fibrocytes in the lateral wall of the cochlea, which leads to reduced endocochlear potential. Highly positive endocochlear potential is critical for sensory hair cell mechanotransduction and hearing. In this context, here, we propose to develop a therapeutic approach in male Pou3f4 −/y mice based on an adeno-associated viral (AAV) vector-mediated gene transfer in cochlear spiral ligament fibrocytes. Among a broad range of AAV vectors, AAV7 was found to show a strong tropism for the spiral ligament. Thus, we suggest that an AAV7mediated delivery of Pou3f4 complementary DNA in the spiral ligament of Pou3f4 −/y mice could represent an attractive strategy to prevent fibrocyte degeneration and to restore normal cochlear functions and properties, including a positive endocochlear potential, before hearing loss progresses to profound deafness.

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“…However, female carriers may have varying degrees of hearing threshold changes, mild semicircular canal dilatation and postural abnormalities (37). In previous years, genetic sequencing of families with DFN3 has revealed that almost all affected individuals have Brn4 gene segments with nonsense, missense or frameshift mutations, and even de novo genome deletion, thus resulting in abnormal protein structure and function (37)(38)(39)(40)(41)(42)(43)(44). Chromosome translocations and deletions have also been detected upstream of Brn4 (up to 900 kb upstream), suggesting that some cis-regulatory elements may be present in these regions to regulate the gene expression (45).…”

Section: Related Biological Processes Of Brn4mentioning

confidence: 99%

Research progress of the transcription factor Brn4 (Review)

Zhang

Wang

et al. 2020

Mol Med Rep

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A novel pathogenic variant c.975G>A (p.Trp325*) in the POU3F4 gene in Yakut family (Eastern Siberia, Russia) with the X-linked deafness-2 (DFNX2)

Cited by 8 publications

References 33 publications

Spectrum of Genes for Non-GJB2-Related Non-Syndromic Hearing Loss in the Russian Population Revealed by a Targeted Deafness Gene Panel

Spectrum of Genes for Non-GJB2-Related Non-Syndromic Hearing Loss in the Russian Population Revealed by a Targeted Deafness Gene Panel

Considering gene therapy to protect from X‐linked deafness DFNX2 and associated neurodevelopmental disorders

Research progress of the transcription factor Brn4 (Review)

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