Biology Reference
In-Depth Information
5.3.1.2 Waardenburg Syndrome Types 3 and 4
Other Waardenburg syndrome subtypes include type III Waardenburg
syndrome (WS3; OMIM 148820), also known as Klein-Waardenburg syn-
drome. Most WS3 cases appear to be sporadic, whereas familial cases
usually demonstrate autosomal-dominant inheritance. The phenotype of
WS3 is composed of the WS1 phenotype in combination with hypoplastic
muscles and contractures of the upper limbs. The phenotype of type IV
Waardenburg syndrome (WS4; OMIM 277580), or Shah-Waardenburg syn-
drome, is a combination of the WS2 phenotype with Hirschsprung disease
(Shah et al. 1981). The hallmark of Hirschsprung disease is colonic obstruc-
tion and dilation caused by a lack of autonomic nervous innervation to the
colon.
5.3.2 Genetics of Waardenburg Syndrome
5.3.2.1 Mutations of PAX3 Associated with WS1, WS3 and CDHS
WS1 was mapped to chromosome 2q based upon an initial observation of
a
de novo
chromosomal inversion on 2q in a WS1 patient (Ishikiriyama
et al. 1989), followed by demonstration in two families of linkage of WS1
to the placental alkaline phosphatase locus on 2q (Asher et al. 1991; Foy et
al. 1990). As predicted by Asher and Friedman (1990), comparison of the
map position of WS1 with the syntenic mouse region suggested a possible
mouse homologue, the
Splotch
mutation (Foy et al. 1990). This hypothesis
was confirmed by several groups demonstrated
PAX3
and
Pax3
mutations
in WS1 patients and the
Splotch
mouse, respectively (Baldwin et al. 1992;
Epstein et al. 1991; Morell et al. 1992; Tassabehji et al. 1992).
PAX3
(orig-
inally called
HuP2
) contains 10 exons encoding a transcription factor with
two DNA-binding domains, a paired-domain and a paired-type home-
odomain (Barber et al. 1999). Expression studies in the developing mouse
demonstrate concentrated
Pax3
expression in the neural crest, as well as
neural crest-derived structures (Goulding et al. 1991). The neural crest
contributes to glial cells in the spiral ganglion and auditory nerve, as well
as the melanocytes of the stria vascularis. Mouse
Pax3
is known to be
expressed in developing limb buds (Bober et al. 1994), as predicted by the
upper limb abnormalities observed in WS3.
Most, if not all, cases of WS1 map to the
PAX3
locus on chromosome
2q3. Over 50 different mutations have been described, and different fami-
lies usually have different mutations (DeStefano et al. 1998). With the likely
exception of missense mutations of codon 47 discussed below, most
premature-termination and amino-acid-substitution mutations are pre-
dicted to cause loss-of-function and, therefore, act via haploinsufficiency.
Read and Newton recently reviewed Waardenburg syndrome and favored
a protein-dosage hypothesis to explain the reduced penetrance and vari-
able expressivity of the WS1/WS3 phenotypes (Read and Newton 1997).
