Biology Reference
In-Depth Information
They postulated that effective levels of
PAX3
protein are dependent upon
the
PAX3
genotype in combination with variations in the host cellular
responses to
PAX3
. Any reduction of
PAX3
dosage would result in dystopia
canthorum, whereas further decreases would cause, in progression, pig-
mentation abnormalities, limb abnormalities as seen in WS3 patients, and
neural tube defects (Read and Newton 1997). This mechanism probably
does not fully account for the deafness phenotype, since there is evidence
that other genes, perhaps
PAX3
target genes, modify its expression (Morell
et al. 1997).
Most WS3 individuals are heterozygous for
PAX3
mutations (Sheffer and
Zlotogora 1992). A consanguineous marriage between two WS1 individuals
heterozygous for a
PAX3
missense mutation, S84F, produced a deaf child
homozygous for S84F who had dystopia canthorum, partial albinism, and
severe upper-limb defects characteristic of WS3 (Zlotogora et al. 1995).
Another patient with a phenotype similar to that of WS3 had an intersti-
tial deletion, del(2)(q35-q36), that included
PAX3
and
COL4A3
(Pasteris
et al. 1993). In a well studied WS3 family with four affected patients
(Goodman et al. 1982; Sheffer and Zlotogora 1992), Hoth and coworkers
(1993) identified an asparagine-to-histidine substitution (N47H) within the
paired DNA binding domain of
PAX3
.
Craniofacial-Deafness-Hand-Syndrome (CDHS, MIM 122880) is a syn-
drome that resembles the WS3 phenotype. In one family, CDHS is charac-
terized by profound sensorineural hearing loss, absence or hypoplasia of
the nasal bones, hypoplastic maxilla, small and short nose with thin nares,
limited wrist mobility, short palpebral fissures, ulnar deviation of the fingers,
and hypertelorism (Sommer et al. 1983). Absence or hypolasia of nasal
bones was not observed in the WS3 family previously described (J. Zloto-
gora, personal communication). In the CDHS family, a missense mutation
in codon 47 of
PAX3
, N47K, was identified (Asher et al. 1996). If the N47H
mutation associated with WS3 and the N47K mutation in the CDHS family
are both loss-of-function mutations, the phenotypic distinction between
WS3 and CDHS, including nasal bone hypoplasia in CDHS, must be due to
different alleles of modifying genes in these families. An alternative expla-
nation is that not all mutations of
PAX3
are null alleles, and the phenotypic
differences between CDHS and WS3 may be due to altered
PAX3
tran-
scriptional properties as a consequence of the different substitutions at
amino acid residue 47. N47H and N47K could differentially alter the inter-
action between the
PAX3
protein and a subset of its downstream target
genes. This latter hypothesis may be tested when more of the
PAX3
target
genes are identified.
5.3.2.2 WS2, WS2 with AROA and Tietz-Smith Syndrome
The WS2 phenotype in one kindred was mapped to chromosome 3q12-p14
by Hughes et al. (Hughes et al. 1994). This was known to be the location
of the human orthologue,
MITF
, of the mouse microphthalmia gene
mi
