The gene for X-linked progressive mixed deafness with perilymphatic gusher during stapes surgery (DFN3) is linked to PGK

Brunner, Han G.; Bennekom, C. A. van; Lambermon, Eric; Oei, T. L.; Cremers, C.W.R.J.; Wieringa, Bé; Ropers, Hans‐Hilger

doi:10.1007/bf00273647

Cited by 55 publications

(22 citation statements)

References 12 publications

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“…Cloning of the POU3F4 Gene The DFN3 gene was mapped to the proximal part of Xq by genetic linkage analyses of large families [11,12] and by the identification of microscopically visible Xq21 deletions that are associated with complex phenotypes consisting of choroideremia, non-specific mental retardation and DFN3 [13][14][15][16]. Subsequently, smaller sized deletions were found in patients with classic DFN3 [17,18], and the underlying gene, encoding a POU domain transcription factor, class III, factor 4 (POU3F4), was identified by a positional candidate gene cloning approach [19].…”

Section: Mutation Spectrum In Dfn3mentioning

confidence: 99%

The Ins and Outs of X-Linked Deafness Type 3

Cremers¹,

Cremers²,

Ropers³

2000

Advances in Oto-Rhino-Laryngology

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The most frequent form of X-linked deafness, deafness type 3 (DFN3) is characterized by temporal bone abnormalities, stapes fixation, and, in most cases, a mixed type of deafness. The physical fine mapping of (micro)deletions associated with classic DFN3 enabled the positional cloning of the underlying gene, POU3F4. Missense mutations identified in the POU3F4 gene of DFN3 patients are conspicuously clustered in the 3-helix of the POU homeodomain, suggesting that missense mutations outside the POU domains result in a different phenotype. Surprisingly, the POU3F4 gene was situated outside several microdeletions associated with DFN3 and detailed analysis of the proximal region led to the identification of several DFN3-associated microdeletions 900 kb upstream of POU3F4. In addition, we identified a DFN3-associated paracentric inversion (q21.1q21.31) in which one of the inversion breakpoints is located 170 kb proximal to POU3F4. The smallest proximal deletion, which is contained in all other proximal deletions except one, merely spans 8 kb and contains non-transcribed but highly conserved sequences. These findings might be explained by the presence of a long-range transcriptional regulation element, possibly an enhancer, 900 kb proximal to POU3F4. Spatiotemporal expression studies indicate that POU3F4 does not only play an important role in otogenesis, but also in brain, kidney and muscle development. In addition, POU3F4 expression was detected in the adult mouse heart and pancreatic -cells. The absence of overt clinical features in DFN3 patients outside the temporal bone suggests that there is a high degree of functional redundancy among different members of the POU domain superfamily.

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Section: Mutation Spectrum In Dfn3mentioning

confidence: 99%

The Ins and Outs of X-Linked Deafness Type 3

Cremers¹,

Cremers²,

Ropers³

2000

Advances in Oto-Rhino-Laryngology

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“…A de novo chromosomal inversion, inv(2)(q35q37.3), in a sporadic case of Waardenburg syndrome type 1 (WS1), an autosomal dominant disorder characterized by dystopia canthorum, pigmentary abnormalities of the skin, hair and ocular fundus and sensorineural deafness, was invaluable in focusing genetic linkage analyses in this region of chromosome 2 [Ishikiriyama et al, 1989]; assignment of WS1 to 2q37 [Foy et al, 1990] and identification of mutations in PAX3 [Tassabehji et al, 1992] followed shortly thereafter. Identification of the role of POU3F4 in X-linked progressive mixed deafness with perilymphatic gusher was aided by recognition of cytogenetically visible deletions in Xq13-q21.1 [Brunner et al, 1988;Wallis et al, 1988]. Several Smith-Magenis syndrome patients who have sensorineural hearing loss (SHL) and deletion of one allele of MYO15 have been found to have a point mutation in the remaining allele of MYO15 [Liburd et al, 2001].…”

Section: Introductionmentioning

confidence: 98%

Methylthioadenosine phosphorylase (MTAP) in hearing: Gene disruption by chromosomal rearrangement in a hearing impaired individual and model organism analysis

Williamson

Darrow

Michaud

et al. 2007

American J of Med Genetics Pt A

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Genes with a role in the auditory system have been mapped by genetic linkage analysis of families with heritable deafness and then cloned through positional candidate gene approaches. Another positional method for gene discovery is to ascertain deaf individuals with balanced chromosomal translocations and identify disrupted or disregulated genes at the site(s) of rearrangement. We report herein the use of fluorescence in situ hybridization (FISH) to map the breakpoint regions on each derivative chromosome of a de novo apparently balanced translocation, t(8;9)(q12.1;p21.3)dn, in a deaf individual. Chromosomal breakpoints were assigned initially by GTG-banding of metaphase chromosomes and then BAC probes chosen to map precisely the breakpoints by FISH experiments. To facilitate cloning of the breakpoint sequences, further refinement of the breakpoints was performed by FISH experiments using PCR products and by Southern blot analysis. The chromosome 9 breakpoint disrupts methylthioadenosine phosphorylase (MTAP); no known or predicted genes are present at the chromosome 8 breakpoint. Disruption of MTAP is hypothesized to lead to deafness due to the role of MTAP in metabolizing an inhibitor of polyamine synthesis. Drosophila deficient for the MTAP ortholog, CG4,802, were created and their hearing assessed; no hearing loss phenotype was observed. A knockout mouse model for MTAP deficiency was also created and no significant hearing loss was detected in heterozygotes for Mtap. Homozygous Mtap-deficient mice were embryonic lethal.

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“…Sex linked and mitochondrial hearing impairment [40,41,42] were not diagnosed in any of the children of our cohort.…”

mentioning

confidence: 61%

Etiological diagnosis of bilateral, sensorineural hearing impairment in a pediatric Greek population

Riga

Psarommatis

Lyra

et al. 2005

International Journal of Pediatric Otorhinolaryngology

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The gene for X-linked progressive mixed deafness with perilymphatic gusher during stapes surgery (DFN3) is linked to PGK

Cited by 55 publications

References 12 publications

The Ins and Outs of X-Linked Deafness Type 3

The Ins and Outs of X-Linked Deafness Type 3

Methylthioadenosine phosphorylase (MTAP) in hearing: Gene disruption by chromosomal rearrangement in a hearing impaired individual and model organism analysis

Etiological diagnosis of bilateral, sensorineural hearing impairment in a pediatric Greek population

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