Biology Reference
In-Depth Information
(Asher and Friedman 1990; Tachibana et al. 1994). Both
MITF
and
mi
encode a basic helix-loop-helix leucine zipper transcription factor. A variety
of
mi
alleles exists that cause abnormalities of mast cells, teeth, osteopet-
rosis, or coat color (Steingrimsson et al. 1994). The
mi
protein forms dimers
that can bind to the M box, a presumed cis-regulatory DNA sequence
located upstream of several melanocyte-specific genes (Hemesath et al.
1994), suggesting that
mi/MITF
may be a master switch controlling
melanocyte development. Finally,
PAX3
transactivates the
MITF
gene in
624 mel human melanoma cells in vitro, and WS1 mutations in the paired
box or homeodomain of
PAX3
prevent binding and activation of the
MITF
promoter (Watanabe et al. 1998). These in vitro results predict that tran-
scription of the
mi
gene would be reduced in vivo by the
Pax3
mutation in
the
Splotch
mouse.
The existence of other WS2 loci is suggested by the detection of
MITF
mutations in only a minority of WS2 families studied to date. The reported
MITF
mutations appear to indicate a haploinsufficiency mechanism. All the
MITF
mutations have been associated with the typical WS2 phenotype, with
two exceptions. The first is a single family with Tietz-Smith syndrome
(Table 6.5), whose phenotype comprises sensorineural hearing loss and
uniform pigmentation dilution. The second exception is a family with an
atypical phenotype comprising WS2 features in conjunction with autosomal
recessive ocular albinism (AROA; Table 6.5) (Bard 1978; Morell et al.
1997). The phenotype in this family was associated with a heterozygous
MITF
frameshift mutation in combination with a homozygous or het-
erozygous temperature-sensitive common polymorphism (
TYR
R402Q
) in the
tyrosinase gene (
TYR
) that results in reduced tyrosinase catalytic activity.
Heterozygotes and homozygotes for
TYR
R402Q
are phenotypically normal.
However, compound heterozygotes between
TYR
R402Q
and recessive
mutant alleles of
TYR
may have the AROA phenotype (Fukai et al. 1995).
Morell and co-workers (1997) hypothesized that haploinsufficiency for
MITF
, the consequent down-regulation of
TYR
and the homozygosity or
heterozygosity for
TYR
R402Q
results in the WS2 and AROA phenotype. This
WS2 + AROA family is an example of digenic inheritance (Morell et al.
1997).
5.3.2.3 Molecular Genetics of WS4
Recent studies have established the molecular basis for WS4, or Shah-
Waardenburg syndrome. Initial clinical observations indicated that WS4
inheritance is autosomal-recessive (Shah et al. 1981). More recent studies
have shown that homozygous mutations in the endothelin-B receptor gene
EDNRB
can cause the WS4 phenotype (Attie et al. 1995; Puffenberger
et al. 1994), whereas heterozygotes are normal or have Hirschsprung's
disease alone (Amiel et al. 1996; Kusafuka et al. 1996). Homozygous muta-
tions in the
EDN3
gene encoding the ligand for the endothelin-B receptor,
endothelin-3, may also be associated with WS4 (Edery et al. 1996; Hofstra
