Diagnostics Service of
the Molecular Otolaryngology & Renal Research Laboratories is a Joint
Commission-approved CLIA-accredited diagnostic laboratory that
offers mutation screening of several genes.
DFN3 (OMIM#: #
Deafness at the DFN3 locus can be conductive (due
to impaired stapes mobility) and/or mixed with a superimposed,
often progressive, sensorineural component. Stapedectomy to
correct the conductive component is contraindicated because of
the possibility of iatrogenic profound hearing loss secondary to
a stapes gusher. A stapes gusher occurs because the internal
auditory canal is abnormally dilated. The wide communication
between the internal auditory canal and inner ear can often be
visualized by computerized tomography. The gene, POU3F4,
was found to be responsible for this form of X-linked hearing
loss by De Kok and colleagues.
POU3F4 (OMIM#: #300039)
The single exon of POU3F4 encodes
a transcription factor with a 75 amino acid POU domain and a 63
amino acid homeobox domain. In animal studies, Minowa and
colleagues showed Brn4 (Pou3f4)
deficient mice have profound deafness and inner ear
abnormalities. In humans with DFN3, mutations have been found in
either of the two binding domains, as well as upstream of POU3F4.
In the presence of these large upsteam deletions, the coding
sequence of POU3F4 can
be entirely normal.
MORL screening methodology
Screening for POU3F4 is
performed by sequencing and STRP analysis. The initial screening
test uses oligonucleotide primers that amplify the exon of POU3F4 followed
by direct sequencing to determine whether mutations lie within
the POU3F4 gene.
In the absence of a POU3F4 coding
mutation, the upstream region of POU3F4 is
screened for a possible deletion by running 8 STSs that cover
approximately 1200 kB of genomic DNA at regularly spaced
intervals. These markers are PCR amplified, resolved by gel
electrophoresis and scored as present or absent.
Sensitivity is greater than 99% for coding
sequence analysis of POU3F4.
The sensitivity of the deletion screen is unknown (see Vore et
al., 2005 for a review).
Turn around time is approximately 3 months
(Average TAT - 44 days).
Indications for screening
This test is appropriate for persons with
X-linked nonsydromic hearing loss. Computed tomography of the
temporal bones may show pseudo-Mondini stage II dysplasia, which
includes hypoplasia of the cochlea and dilation of the internal
GeneTests GeneReviews – Deafness and
Hereditary Hearing Loss: Overview
Phelps, P. D. et al.: X-linked
deafness, stapes gushers and a distinctive defect of the inner
33: 326-330, 1991.
PubMed ID: 1922747
De Kok, Y. J. M. et al.: Association
between X-linked mixed deafness and mutations in the POU domain
gene POU3F4. Science
267: 685-688, 1995.
PubMed ID: 7839145
Minowa, O.: Altered
cochlear fibrocytes in a mouse model of DFN3 nonsyndromic
Science 285: 1408-1411, 1999.
PubMed ID: 10464101
Vore, A. P., et al.: Deletion
of and novel missense mutation in POU3F4 in 2 families
segregating X-linked nonsyndromic deafness.
Arch Otolaryngol Head Neck Surg. 2005 Dec;131(12):1057-63
PubMed ID: 16365218