Biology Reference
In-Depth Information
degeneration (as long as hair cell degeneration, rather than hair cell dys-
function, is the cause of the hearing loss, which is not necessarily the case
in genetic deafness).
2.1 Middle Ear and Pinna Defects
In humans with syndromic hearing impairment, pinna defects are some-
times associated with middle ear defects, so it seems useful to consider these
two parts together. The outer and middle ear has a complex developmen-
tal origin, with contributions from all three germ layers (endoderm, ecto-
derm, and mesoderm) and from the first and second branchial arches. A
groove in the surface ectoderm extends inwards to meet an extension of
the pharyngeal endoderm, and the two pockets meet to form the two cell
layers of the tympanic membrane. The three middle ear ossicles (malleus,
incus and stapes) form from condensation of mesenchymal cells within the
pharyngeal pouch, which eventually loses its excess mesenchyme to form
an air-filled recess, the middle ear, linked to the pharynx by the remains of
the endodermal extension, the Eustachian tube. Neural crest cells migrate
to fill the branchial arches in early development, and the first branchial arch
contributes to the pinna, incus, malleus, and tympanic membrane, while the
second arch contributes to the pinna, incus, malleus, and stapes. This com-
plexity means that it is not surprising that many genes involved in cranio-
facial development are important for development of the outer and middle
ear, leading to specific anomalies when the gene is interrupted by knock-
out techniques. These anomalies are wide-ranging in effect, including minor
differences such as small pinnae, smaller oval windows or minor malfor-
mation of ossicles, through duplication of ossicle primordia or incomplete
tympanic rings, to major malformation of the entire area. Table 8.1 gives
details of many of the reported pinna and middle ear defects in mutants,
and Figure 8.1 (Fekete 1999) illustrates the location of the defects in several
of the mutants. It is noteworthy that many of the knock-out mutants
included in the table have such severe craniofacial defects that they die at
an early stage, often just after birth. So far, only two appear to represent
mutations in genes involved in human deafness,
Eya1
and
Pou3f4
.
Eya1
is
the mouse version of the gene underlying Branchio-Oto-Renal syndrome
(BOR), which shows variable middle ear malformation and mixed hearing
impairment (Abdelhak et al. 1997).
Pou3f4
is the mouse orthologue of the
gene involved in X-linked deafness with gusher, in which middle ear surgery
to release an apparently fixed stapes results in a gush of fluid from the oval
window, a consequence of an inner ear malformation that prevents the
separation of inner ear perilymph from cerebrospinal fluid (de Kok et al.
1995). The mouse knockout shows some similar inner ear malformations
(Phippard et al. 1999), and has also been found to have reduced endo-
cochlear potentials (discussed later). Interestingly, deletion analysis in
humans reveals a regulatory region far upstream of the coding region of
