Biology Reference
In-Depth Information
5.5.2 Genetics of Alport Syndrome
Type IV collagen is a distinct collagen found only in basement membranes,
where it is a predominant component. It is composed of three of six dif-
ferent polypeptide subunits (a1-a6) which assemble into triple helices
(Table 6.6). The “classical” a1 and a2 chains comprise a [a1]
2
a2(IV) het-
erotrimer and a [a1]
3
(IV) homotrimer which are ubiquitously expressed in
all basement membranes. The “novel” a3(IV), a4(IV), a5(IV), and a6(IV)
subunits have restricted tissue distribution and are quantitatively minor
components of the basement membrane. The basement membranes of
the inner ear, glomerulus, and eye are composed of two separate type IV
collagen networks. One network is composed of the a1 and a2 hetero-
trimers, while the other network is composed of tissue-specific combina-
tions of the other subunits. The extracellular triple helices organize via their
noncollagenous amino terminal and carboxy terminal domains into a sup-
ramolecular lattice structure. Other basement membrane components
such as laminin and heparin sulfate proteoglycan then assemble onto this
framework.
The X-linked form of Alport syndrome is associated with mutations in
the
COL4A5
gene (chromosome Xq22) encoding the a5 subunit of type IV
collagen (Barker et al. 1990). There were over 160 different Alport syn-
drome mutations detected in
COL4A5
at the time this topic was reviewed
in 1997 (Lemmink et al. 1997). Most mutations were either point substitu-
tions or deletions of variable portions of the
COL4A5
gene, although larger
deletions have also been reported (Lemmink et al. 1997).
In cases of parental consanguinity and equal affection status in males and
females, autosomal inheritance is likely. The mapping of the type IV colla-
gen genes
COL4A3
and
COL4A4
to chromosome 2q35-q37 suggested that
they may account for autosomally inherited Alport syndrome (Mariyama
et al. 1992; Turner et al. 1992).
COL4A3
and
COL4A4
are closely linked
to each other in a head-to-head orientation on chromosome 2q35-q37
(Mariyama et al. 1992; Turner et al. 1992). Detection of linkage to this
region and the identification of homozygous or compound heterozygous
mutations in one of either of these genes established the molecular basis
for autosomal forms of this disorder (Boye et al. 1998; Lemmink et al. 1994;
Mochizuki et al. 1994).
5.5.3 Pathogenesis of Hearing Loss in Alport Syndrome
The identification of mutations in
COL4A3
,
COL4A4
and
COL4A5
pro-
vides a critical step toward elucidating the cause and pathogenesis of sen-
sorineural hearing loss in this disorder. Immunohistochemical studies of
type IV collagen expression of the murine cochlea demonstrated expres-
sion of
Col4a3
,
Col4a4
, and
Col4a5
in the interdental cells of the sulcus, the
inner sulcus, basilar membrane, and the spiral ligament (Cosgrove et al.
1996).
Col4a5
was also heavily expressed and
Col4a3
was weakly expressed
