1: Nat Genet. 1994 Aug;7(4):509-12.
A gene for Waardenburg syndrome type 2 maps close to the
human homologue of the microphthalmia gene at
chromosome 3p12-p14.1.
Hughes AE, Newton VE, Liu XZ, Read AP.
Department of Medical Genetics, Belfast City Hospital, UK.
Waardenburg syndrome (WS), an autosomal dominant syndrome of hearing loss and
pigmentary disturbances, comprises at least two separate conditions. WS type 1 is
normally caused by mutations in PAX3 located at chromosome 2q35 and is distinguished
clinically by minor facial malformations. We have now located a gene for WS type 2.
Two families show linkage to a group of microsatellite markers located on chromosome
3p12-p14.1. D3S1261 gave a maximum lod score of 6.5 at zero recombination in one
large Type 2 family. In a second, smaller family the adjacent marker D3S1210 gave a lod
of 2.05 at zero recombination. Interestingly, the human homologue (MITF) of the mouse
microphthalmia gene, a good candidate at the phenotypic level, has recently been mapped
to 3p12.3-p14.4.
Whereas classic Waardenburg syndrome (193500) has been proven to be due to mutations in the
PAX3 gene (606597), a few type II families that have been studied have failed to show linkage
to ALPP (171800) and/or PAX3 on 2q37 (Farrer et al., 1992; Tassabehji et al., 1993). See
193500.0006 for a description of a family in which a PAX3 mutation was found in association
with a presumed WS2 phenotype.
In a study of 2 families with WS type II, Hughes et al. (1994) demonstrated linkage to a group of
microsatellite markers located on 3p14.1-p12. D3S1261 gave a maximum lod score of 6.5 at 0.0
recombination in 1 large type II family. In a second, smaller family, the adjacent marker
D3S1210 gave a lod score of 2.05 at 0.0 recombination. The human homolog of the mouse
microphthalmia gene (MITF; 156845) maps to the same region. Asher and Friedman (1990) had
pointed out that because of phenotypic similarities, microphthalmia (mi) is a possible model for
Waardenburg syndrome; there are many mi alleles, some dominant and others recessive, which
interact and complement in various ways, giving a range of phenotypes that can include white
coat, premature graying, unpigmented eyes, and hearing loss. Tassabehji et al. (1994)
demonstrated mutations in the MITF gene in patients with type II Waardenburg syndrome.
Not unexpectedly, Hughes et al. (1994) found that WS2 is heterogeneous, with mutations at
different loci in different families. They suggested that the type II Waardenburg syndrome
mapping to 3p13 be named WS2A and the unlinked form(s) provisionally designated WS2B. In
a personally studied series of 81 individuals from 21 families with WS type II in comparison
with 60 personally studied patients from 8 families with type I, Liu et al. (1995) concluded that
sensorineural hearing loss (77%) and heterochromia iridum (47%) were more common in WS
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type II than in type I. On the other hand, white forelock and skin patches were more frequent in
type I.
: Nat Genet. 1998 Feb;18(2):171-3.
SOX10 mutations in patients with WaardenburgHirschsprung disease.
Pingault V, Bondurand N, Kuhlbrodt K, Goerich DE, Préhu MO, Puliti A,
Herbarth B, Hermans-Borgmeyer I, Legius E, Matthijs G, Amiel J, Lyonnet S,
Ceccherini I, Romeo G, Smith JC, Read AP, Wegner M, Goossens M.
INSERM U468, Hôpital Henri Mondor, Creteil, France.
Waardenburg syndrome (WS; deafness with pigmentary abnormalities) and
Hirschsprung's disease (HSCR; aganglionic megacolon) are congenital disorders caused
by defective function of the embryonic neural crest. WS and HSCR are associated in
patients with Waardenburg-Shah syndrome (WS4), whose symptoms are reminiscent of
the white coat-spotting and aganglionic megacolon displayed by the mouse mutants Dom
(Dominant megacolon), piebald-lethal (sl) and lethal spotting (ls). The sl and ls
phenotypes are caused by mutations in the genes encoding the Endothelin-B receptor
(Ednrb) and Endothelin 3 (Edn3), respectively. The identification of Sox10 as the gene
mutated in Dom mice (B.H. et al., manuscript submitted) prompted us to analyse the role
of its human homologue SOX10 in neural crest defects. Here we show that patients from
four families with WS4 have mutations in SOX10, whereas no mutation could be
detected in patients with HSCR alone. These mutations are likely to result in
haploinsufficiency of the SOX10 product. Our findings further define the locus
heterogeneity of Waardenburg-Hirschsprung syndromes, and point to an essential role of
SOX10 in the development of two neural crest-derived human cell lineages.
WAARDENBURG-SHAH SYNDROME
Alternative titles; symbols
WAARDENBURG SYNDROME, TYPE IV; WS4
WAARDENBURG-HIRSCHSPRUNG DISEASE
WAARDENBURG SYNDROME VARIANT
SHAH-WAARDENBURG SYNDROME
HIRSCHSPRUNG DISEASE WITH PIGMENTARY ANOMALY
Gene map locus 22q13, 20q13.2-q13.3, 13q22
2
TEXT
A number sign (#) is used with this entry because the phenotype can be caused by mutation in
the endothelin-B receptor gene (EDNRB; 131244), in the gene for its ligand, endothelin-3
(EDN3; 131242), or in the SOX10 gene (602229).
DESCRIPTION
Waardenburg-Shah syndrome (WS4) is a disorder of the embryonic neural crest that combines
clinical features of Waardenburg syndrome (see 193500) and Hirschsprung disease (142623).
CLINICAL FEATURES
Shah et al. (1981) reported studies of 5 families in which a total of 12 babies (7 male; 5 female)
with white forelock and white eyebrows and eyelashes presented in the neonatal period with
intestinal obstruction. Eight patients had isochromia irides (light brown irides with mosaic
pattern); in the other 4, information was not recorded. In 6 patients in whom the observations
were recorded, no dystopia canthorum, broad nasal root, or white skin patches were found.
Deafness could not be detected in any of the patients. Microcolon was noted in patients in whom
contrast enemas were done. At operation, the proximal ileum was dilated with collapse of the
distal ileum and colon in 8; operative notes were not available on the other 4. The 12 infants died
3 to 38 days after birth because of failure of the ileostomy to function. This disorder appeared to
be clinically and genetically distinct from Waardenburg syndrome, which has a different
pigmentary anomaly of the eye and usually does not have associated Hirschsprung disease,
although the short segment type may rarely occur in WS.
In 3 of 6 Mexican sibs, Liang et al. (1983) observed Hirschsprung disease in association with
'bicolored' irides. They used the term bicolored rather than heterochromia to emphasize that 2
distinct colors were present in the same iris. The unaffected parents were related, suggesting
autosomal recessive inheritance. Liang et al. (1983) suggested a defect in the neural crest.
Kulkarni et al. (1989) described 3 sibs derived from an uncle-niece marriage who had white
forelock, light-colored irides, white eyelashes, multiple hypopigmented skin patches, and
obstructive ileal lesions.
Edery et al. (1996) reported a 4-year-old girl, born to unrelated parents, with total colonic
aganglionosis, bilateral sensorineural hearing loss, and pigmentary anomalies, including
achromic patches of the skin, white eyelashes, pale blue retina, but absence of dystopia
canthorum found in Waardenburg syndrome.
INHERITANCE
Shah et al. (1981) reported parental consanguinity in 2 of 5 affected families as well as multiple
affected sibs of both sexes in families, suggesting autosomal recessive inheritance. One family
was ascertained through a first cousin of a patient with WS4; this proband had white forelock
3
and heterochromia iridis, but no dystopia canthorum or deafness, as in classic Waardenburg
syndrome.
Badner and Chakravarti (1990) analyzed the 5 families reported by Shah et al. (1981) and
Ambani (1983). Because 2 of the families demonstrated parental consanguinity, autosomal
recessive inheritance had been suggested. Badner and Chakravarti (1990) concluded, however,
that a single dominant gene with pleiotropic effects, with a more severe phenotype in
homozygotes, was more plausible.
MAPPING
Van Camp et al. (1995) reported a patient with characteristics of Waardenburg syndrome type 2
(see WS2A; 193510) and a de novo interstitial deletion of 13q. The authors also described
another family in which 2 sibs had WS2 and Hirschsprung disease; in this family, there was
evidence for a disease locus on chromosome 13q.
MOLECULAR GENETICS
Puffenberger et al. (1994) reported an extensive Mennonite kindred with many cases of
Hirschsprung disease (600155). In individuals with Hirschsprung disease as well as bicolored
irides (6.3%), hypopigmentation (2.5%), sensorineural hearing loss (5.1%), and white forelock
(7.6%) suggestive of WS4, Puffenberger et al. (1994) identified a mutation in the EDNRB gene
(131244.0001). The mutation was found to be dose sensitive, in that the homozygotes and
heterozygotes had a 74% and a 21% risk, respectively, of developing Hirschsprung disease.
In a patient with WS4, Edery et al. (1996) identified a homozygous substitution/deletion
mutation of the EDN3 gene (131242.0001). In a child with WS4, Pingault et al. (2001) identified
a heterozygous nonsense mutation in the EDN3 gene (131242.0007). Three unaffected relatives
and a fetus terminated at 29 weeks' gestation because of intestinal obstruction also had the
mutation. The fetus was found to have Hirschsprung disease affecting the ileum and colon, but
no features of Waardenburg syndrome.
ANIMAL MODEL
In the mouse, at least 3 megacolon genes are associated with pigmentary abnormalities
(8,7:Lane, 1966, 1984).
Defects in the gene encoding the endothelin-B receptor result in aganglionic megacolon and
pigmentary disorders in mice and humans. Baynash et al. (1994) found that targeted disruption of
the mouse endothelin-B ligand (Edn3) gene produces a similar recessive phenotype of
megacolon and coat color spotting.
Southard-Smith et al. (1998) identified Sox10 as the gene underlying the Dom Hirschsprung
mouse model.
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Matsushima et al. (2002) described a novel mutant mouse with a mutation in the Ednrb gene and
proposed the mouse as an animal model of Waardenburg syndrome type IV. These mutants had a
mixed genetic background and extensive white spotting. They died between 2 and 7 weeks after
birth owing to megacolon; their colon distal to the megacolon lacked Auerbach plexus cells.
These mutants did not respond to sound, and the stria vascularis of their cochleas lacked
intermediate cells, i.e., neural crest-derived melanocytes. The inheritance was autosomal
recessive as in human WS4. Breeding analysis revealed that WS4 mice are allelic with piebaldlethal and JF1 mice, which are also mutated in the Ednrb gene. Mutation analysis showed that
the Ednrb gene lacked 318 nucleotides encoding transmembrane domains owing to deletion of
exons 2 and 3.
1: Nat Genet. 1998 Jan;18(1):72-5.
Links
Rapid cloning of expanded trinucleotide repeat sequences
from genomic DNA.
Koob MD, Benzow KA, Bird TD, Day JW, Moseley ML, Ranum LP.
Department of Neurology, University of Minnesota, Minneapolis 55455, USA.
koobx001@gold.tc.umn.edu
Trinucleotide repeat expansions have been shown to cause a number of
neurodegenerative diseases. A hallmark of most of these diseases is the presence of
anticipation, a decrease in the age at onset in consecutive generations due to the tendency
of the unstable trinucleotide repeat to lengthen when passed from one generation to the
next. The involvement of trinucleotide repeat expansions in a number of other diseases-including familial spastic paraplegia, schizophrenia, bipolar affective disorder and
spinocerebellar ataxia type 7 (SCA7; ref. 10)--is suggested both by the presence of
anticipation and by repeat expansion detection (RED) analysis of genomic DNA samples.
The involvement of trinucleotide expansions in these diseases, however, can be
conclusively confirmed only by the isolation of the expansions present in these
populations and detailed analysis to assess each expansion as a possible pathogenic
mutation. We describe a novel procedure for quick isolation of expanded trinucleotide
repeats and the corresponding flanking nucleotide sequence directly from small amounts
of genomic DNA by a process of Repeat Analysis, Pooled Isolation and Detection of
individual clones containing expanded trinucleotide repeats (RAPID cloning). We have
used this technique to clone the pathogenic SCA7 CAG expansion from an archived
DNA sample of an individual affected with ataxia and retinal degeneration.
1: Nat Genet. 1999 Apr;21(4):379-84.
Comment in:
Nat Genet. 2000 Mar;24(3):213; author reply 215.
Nat Genet. 2000 Mar;24(3):214-5.
Links
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An untranslated CTG expansion causes a novel form of
spinocerebellar ataxia (SCA8)
Koob MD, Moseley ML, Schut LJ, Benzow KA, Bird TD, Day JW, Ranum LP.
Department of Neurology, Institute of Human Genetics, University of Minnesota,
Minneapolis 55455, USA. koobx001@gold.tc.umn.edu
Myotonic dystrophy (DM) is the only disease reported to be caused by a CTG expansion.
We now report that a non-coding CTG expansion causes a novel form of spinocerebellar
ataxia (SCA8). This expansion, located on chromosome 13q21, was isolated directly
from the genomic DNA of an ataxia patient by RAPID cloning. SCA8 patients have
expansions similar in size (107-127 CTG repeats) to those found among adult-onset DM
patients. SCA8 is the first example of a dominant SCA not caused by a CAG expansion
translated as a polyglutamine tract.
: Nat Genet. 1993 Jun;4(2):135-
Direct detection of novel expanded trinucleotide repeats in
the human genome.
Schalling M, Hudson TJ, Buetow KH, Housman DE.
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge 02139.
Expansion of trinucleotide repeats can give rise to genetic disease. We have developed a
technique, repeat expansion detection (RED), that can identify potentially pathological
repeat expansion without prior knowledge of chromosomal location. Human genomic
DNA is used as a template for a two-step cycling process that generates oligonucleotide
multimers when expanded trinucleotide sequences are present at the level found in
myotonic dystrophy and fragile-X patients. We have identified at least one new locus
exhibiting trinucleotide expansion. Analysis of three families transmitting a long CTG
repeat shows that the allele in these families corresponds to a locus on chromosome 18.
RED constitutes a powerful tool to identify other diseases caused by this mechanism,
particularly diseases associated with anticipation.
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