A duplication/paracentric inversion associated with familial X-linked deafness (DFN3) suggests the presence of a regulatory element more than 400 kb upstream of the POU3F4 gene

Kok, Y.J.M. de; Merkx, G.F.M.; Maarel, Silvère M. van der; Huber, I.; Malcolm, Sue; Ropers, H.-H.; Cremers, Frans P.M.

doi:10.1093/hmg/4.11.2145

Cited by 65 publications

(30 citation statements)

References 23 publications

(26 reference statements)

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“…Patient 8 was known to have, next to an inversion inv(X)(q21.1q21.3), a duplication of 150 kb involving the POU3F4 gene on Xq21.1. 24 The size of this duplication as determined by array CGH corresponds well with the original results, and was shown to affect two overlapping BAC clones (figs 2H and I). An additional, as yet unknown, duplication of approximately 240 kb was identified in Xq21.3 (fig 2J).…”

Section: Analysis Of Patients With X Linked Disorderssupporting

confidence: 81%

“…The second patient (patient 8) with an inversion inv(X)(q21.1q21.3) was described to have a duplication of 150 kb, upstream of the POU3F4 gene that causes the DFN3 phenotype. 24 Also in this case, an additional duplication (approximately 240 kb) was found at Xq21.3. These results indicate that the PCDH11X gene must be partially duplicated in this patient.…”

Section: Discussionmentioning

confidence: 56%

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High resolution profiling of X chromosomal aberrations by array comparative genomic hybridisation

Veltman¹,

Yntema²,

Lugtenberg³

et al. 2004

Journal of Medical Genetics

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Section: Analysis Of Patients With X Linked Disorderssupporting

confidence: 81%

Section: Discussionmentioning

confidence: 56%

High resolution profiling of X chromosomal aberrations by array comparative genomic hybridisation

Veltman¹,

Yntema²,

Lugtenberg³

et al. 2004

Journal of Medical Genetics

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“…Deafness type 3 (DFN3) is the most common type of in X chromosome–linked, non-syndromic hearing loss. DFN3 is caused by mutations in Brn4, which is the gene that encodes the POU domain, class 3, transcription factor 4 (POU3F4) [1]. During embryogenesis, Brn4 is expressed in mesenchymal cells of the inner ear [2].…”

Section: Introductionmentioning

confidence: 99%

Deficiency of Transcription Factor Brn4 Disrupts Cochlear Gap Junction Plaques in a Model of DFN3 Non-Syndromic Deafness

et al. 2014

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Brn4, which encodes a POU transcription factor, is the gene responsible for DFN3, an X chromosome–linked, non-syndromic type of hearing loss. Brn4-deficient mice have a low endocochlear potential (EP), hearing loss, and ultrastructural alterations in spiral ligament fibrocytes, however the molecular pathology through which Brn4 deficiency causes low EP is still unclear. Mutations in the Gjb2 and Gjb6 genes encoding the gap junction proteins connexin26 (Cx26) and connexin30 (Cx30) genes, respectively, which encode gap junction proteins and are expressed in cochlear fibrocytes and non-sensory epithelial cells (i.e., cochlear supporting cells) to maintain the proper EP, are responsible for hereditary sensorineural deafness. It has been hypothesized that the gap junction in the cochlea provides an intercellular passage by which K+ is transported to maintain the EP at the high level necessary for sensory hair cell excitation. Here we analyzed the formation of gap junction plaques in cochlear supporting cells of Brn4-deficient mice at different stages by confocal microscopy and three-dimensional graphic reconstructions. Gap junctions from control mice, which are composed mainly of Cx26 and Cx30, formed linear plaques along the cell-cell junction sites with adjacent cells. These plaques formed pentagonal or hexagonal outlines of the normal inner sulcus cells and border cells. Gap junction plaques in Brn4-deficient mice did not, however, show the normal linear structure but instead formed small spots around the cell-cell junction sites. Gap junction lengths were significantly shorter, and the level of Cx26 and Cx30 was significantly reduced in Brn4-deficient mice compared with littermate controls. Thus the Brn4 mutation affected the assembly and localization of gap junction proteins at the cell borders of cochlear supporting cells, suggesting that Brn4 substantially contributes to cochlear gap junction properties to maintain the proper EP in cochleae, similar to connexin-related deafness.

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“…Clinical characteristics of DFN3 in affected males include temporal bone abnormalities, stapes fixation, and, in most cases, a mixed type of hearing loss, which is often progressive (7,8,10). Anatomical anomalies of the temporal bone revealed by computer-assisted tomography (CT) include dilatation of the lateral end of the internal acoustic canal (IAC), abnormally wide communication between the IAC and inner ear compartment, and, sometimes, partial hypoplasia of the cochlea (8, 27).…”

mentioning

confidence: 99%

Clinical and molecular characterizations of novelPOU3F4mutations reveal that DFN3 is due to null function of POU3F4 protein

Lee

Song

Kang

et al. 2009

Physiological Genomics

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UK. Clinical and molecular characterizations of novel POU3F4 mutations reveal that DFN3 is due to null function of POU3F4 protein. Physiol Genomics 39: 195-201, 2009. First published August 11, 2009 doi:10.1152/physiolgenomics.00100.2009.-X-linked deafness type 3 (DFN3), the most prevalent X-linked form of hereditary deafness, is caused by mutations in the POU3F4 locus, which encodes a member of the POU family of transcription factors. Despite numerous reports on clinical evaluations and genetic analyses describing novel POU3F4 mutations, little is known about how such mutations affect normal functions of the POU3F4 protein and cause inner ear malformations and deafness. Here we describe three novel mutations of the POU3F4 gene and their clinical characterizations in three Korean families carrying deafness segregating at the DFN3 locus. The three mutations cause a substitution (p.Arg329Pro) or a deletion (p.Ser310del) of highly conserved amino acid residues in the POU homeodomain or a truncation that eliminates both DNA-binding domains (p.Ala116fs). In an attempt to better understand the molecular mechanisms underlying their inner ear defects, we examined the behavior of the normal and mutant forms of the POU3F4 protein in C3H/10T1/2 mesodermal cells. Protein modeling as well as in vitro assays demonstrated that these mutations are detrimental to the tertiary structure of the POU3F4 protein and severely affect its ability to bind DNA. All three mutated POU3F4 proteins failed to transactivate expression of a reporter gene. In addition, all three failed to inhibit the transcriptional activity of wild-type proteins when both wildtype and mutant proteins were coexpressed. Since most of the mutations reported for DFN3 thus far are associated with regions that encode the DNA binding domains of POU3F4, our results strongly suggest that the deafness in DFN3 patients is largely due to the null function of POU3F4. hearing loss; X-linked deafness type 3; inner ear CONGENITAL HEARING LOSS IS one of the most common sensory disorders in humans, affecting approximately one in 1,000 newborns (24). More than 50% of the congenital hearing loss is due to genetic causes, and the majority of these hereditary cases are nonsyndromic. While most genetic nonsyndromic hearing loss is caused by mutations in autosomal genes, X-linked cases are estimated to comprise between 1 and 5% of these (26). Thus far, four different X-linked nonsyndromic hearing loss loci (DFN2, DFN3, DFN4, and DFN6) have been mapped, but the causative gene has been identified only for the DFN3 locus (33).X-linked deafness type 3 (DFN3) accounts for ϳ50% of all families carrying X-linked nonsyndromic hearing loss (26). Clinical characteristics of DFN3 in affected males include temporal bone abnormalities, stapes fixation, and, in most cases, a mixed type of hearing loss, which is often progressive (7,8,10). Anatomical anomalies of the temporal bone revealed by computer-assisted tomography (CT) include dilatation of the lateral end of the internal acoustic canal (IAC...

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A duplication/paracentric inversion associated with familial X-linked deafness (DFN3) suggests the presence of a regulatory element more than 400 kb upstream of the POU3F4 gene

Cited by 65 publications

References 23 publications

High resolution profiling of X chromosomal aberrations by array comparative genomic hybridisation

High resolution profiling of X chromosomal aberrations by array comparative genomic hybridisation

Deficiency of Transcription Factor Brn4 Disrupts Cochlear Gap Junction Plaques in a Model of DFN3 Non-Syndromic Deafness

Clinical and molecular characterizations of novelPOU3F4mutations reveal that DFN3 is due to null function of POU3F4 protein

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