Biology Reference
In-Depth Information
The majority of reported Stickler syndrome mutations have been in
COL2A1
(Spranger et al. 1994). These dominant mutations are predicted
to cause premature chain termination and are presumed to act via a hap-
loinsufficiency mechanism. In contrast to
COL2A1
, the reported Stickler
syndrome mutations in
COL11A1
and
COL11A2
are generally missense or
in-frame deletion mutations that appear to act via a dominant negative
mechanism (Annunen et al. 1999; Richards et al. 1996; Sirko-Osadsa et al.
1998; Vikkula et al. 1995). The Marshall syndrome phenotype appears to
be specifically associated with either splice-site mutations, or genomic dele-
tions affecting 54 bp exons in the C-terminal half of
COL11A1
(Annunen
et al. 1999; Griffith et al. 1998). In contrast, other mutations in
COL11A1
result in phenotypes with overlapping features of the Marshall and Stick-
ler syndrome (Annunen et al. 1999). It is thought that these mutations of
COL11A1
and
COL11A2
exert their effects via a dominant negative mech-
anism in which the mutant polypeptides can initiate normal association
with wild-type polypeptides via their C-terminal propeptide domains, but
cannot complete proper assembly into a triple helix. The resulting mutant
heterotrimers containing both wild-type and mutant polypeptides may then
undergo abnormal posttranslational modification, secretion, assembly into
fibrils, or degradation (Prockop and Kivirikko 1995).
The genetics of Stickler syndrome illustrate two important general
principles: (1) genetic heterogeneity, in which a phenotype may be associ-
ated with mutations in one of several genes; (2) allelic heterogeneity of
COL11A1
mutations, in which more than one phenotype (the Marshall
or Stickler syndromes) may be associated with mutations in a given gene.
Allelism provides insights into gene structure, function and expression by
providing correlations of more than one observed mutation (genotype)
with a phenotype.
5.1.3 Pathogenesis of Hearing Loss in Stickler Syndrome
Biochemical and immunohistochemical analyses have demonstrated that
type II collagen is expressed in the soft tissue elements of human, rodent,
and avian cochleae (Khetarpal et al., 1994; Yoo and Tomoda, 1988; Ishibe,
1989; Richardson, 1987; Thalmann, 1987), as would be expected, since Stick-
ler syndrome mutations in
COL2A1
can cause sensorineural hearing loss.
Similarly, classical biochemical analyses of microdissected tissue demon-
strated type XI collagen in the tectorial membrane, as well as in the basilar
membrane, of the adult guinea pig (Thalmann 1993). This pattern is
consistent with the pattern of
Col11a1
and
Col11a2
mRNA expression in
embryonic and early postnatal mouse cochleae (McGuirt et al. 1999;
Shpargel and Griffith 2000).
Fibrillar collagens are thought to be important for the observed tensile
strength and compressibility of articular cartilage and other connective
tissues in which they are expressed. It is possible that the Stickler and
