Disease relevance of POU3F4

• 1. By employing pulsed field gel electrophoresis (PFGE) we identified a chromosomal aberration in the DNA of a DFN3 patient who did not show alterations in the open reading frame (ORF) of POU3F4 [1].
• The X-chromosomal breakpoint was located within a region where both the choroideremia locus and a deafness locus (DFN3/POU3F4) have been mapped [2].
• Deafness with fixation of the stapes (DFN3) is the most frequent X-linked form of hearing impairment [3].
• Highlights are the chromosomal localization of at least five genes for autosomal forms of non-syndromic deafness and, more recently, the cloning of an X-linked deafness gene, DFN3, and the Usher syndrome type IB gene [4].
• The first child developed metastasis to the brain 4 years after resection of his adrenal primary and 2 and 1 years, respectively, after metastases to the liver and lungs [5].

High impact information on POU3F4

• In five unrelated patients with DFN3 but not in 50 normal controls, small mutations were found that result in truncation of the predicted protein or in nonconservative amino acid substitutions [3].
• Position effects with cytogenetic rearrangements well outside the coding region have been implicated for four of the genes discussed: POU3F4, SOX9, PAX6, and GL13 [6].
• The DFN3 gene Brain 4 encodes a POU domain containing transcription factor that is involved in the development of the inner ear [4].
• Exposure of stem cell progeny to either IGF-I or BDNF resulted in a rapid upregulation of Brn-4 mRNA and protein [7].
• Further mutations in Brain 4 (POU3F4) clarify the phenotype in the X-linked deafness, DFN3 [8].

Biological context of POU3F4

• In both patients, the missense mutations are situated in the POU homeodomain and are predicted to disrupt the DNA binding of the POU3F4 protein [9].
• Since these domains constitute only 35% of the open reading frame of POU3F4, there is a statistically significant preference for mutations in the POU-specific and POU homeodomain [9].
• All nine point mutations thus far described were found in the POU domains of POU3F4 [9].
• The brain-specific POU-box gene Brn4 is a sex-linked transcription factor located on the human and mouse X chromosomes [10].
• Early in otic embryogenesis, the Brn4 gene product is localized to the nucleus of the vast majority of cells in which it is expressed [11].

Anatomical context of POU3F4

• X-linked deafness with stapes fixation (DFN3) is caused by mutations in the POU3F4 gene at Xq21 [1].
• DESIGN: Computed tomographic study of the temporal bone in probands from each family, followed by mutation screening and deletion mapping of POU3F4 in family members [12].
• The Brn4 gene product remains nuclear in those regions of the otic capsule that eventually give rise to the mature bony labyrinth [11].
• As the otic capsule condenses further and surrounds the entire otic vesicle, the Brn4 gene product is detected throughout the inner ear in the mesenchyme of both the cochlear and vestibular aspects [11].
• Neurons comprising the endocrine hypothalamus develop in tandem with their ultimate target, the pituitary gland, and arise from a primordium in which three related class III POU domain factors-Brn-2, Brn-4, and Brn-1-are initially co-expressed [13].

Associations of POU3F4 with chemical compounds

• RESULTS: Sequencing of the PCR product revealed a 6-base deletion (TTCAAA) at nucleotides 601 to 606, resulting in a two-amino-acid deletion in the POU3F4 protein, (phenylalanine and lysine at amino acid residues 201 and 202) [14].
• RESULTS: In the first family, a large deletion was identified that includes POU3F4 and extends upstream approximately 530 kilobases; in the second family, a novel serine-to-leucine (S228L) amino acid mutation was identified in the POU-specific domain of POU3F4 [12].

Other interactions of POU3F4

• Candidate genes including COL4A5, DIAPH, and POU3F4 were excluded by clinical and molecular analyses [15].
• A novel mutation of POU3F4 causes congenital profound sensorineural hearing loss in a large Chinese family [16].
• The homeodomain transcription factors brain-4, pax-6, and cdx-2 have been shown to bind to these sites and to transactivate glucagon gene expression [17].

Analytical, diagnostic and therapeutic context of POU3F4

• OBJECTIVE: The molecular defect in patients with X-linked mixed deafness showing a perilymphatic gusher at stapedectomy (DFN3) has been attributed to mutations in the POU3F4 gene [14].
• Southern blot analysis indicated that a DNA segment of 150 kb, located 170 kb proximal to the POU3F4 gene, was duplicated [1].
• Indirect immunocytochemistry with Brn-4 antiserum showed that the protein was expressed in newly generated neurons [7].
• Indirect binding, competition, and Western blot analyses indicate that the Mab AEC3A1-9 (3A1), ASSEA-1, and AECAB1-32 (AB1) recognize cell-defined SSEA-1 antigen with activity characteristic of the cell source (HL60 greater than OTF9 greater than K562 much greater than SOTF9) [18].

References