A Gene for Waardenburg Syndrome Type 2 Maps Close to the Human Homologue of the Microphthalmia

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

1 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 Waardenburg- Hirschsprung 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.

4 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 piebald- lethal 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. [email protected]

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. Links Comment in: Nat Genet. 2000 Mar;24(3):213; author reply 215. Nat Genet. 2000 Mar;24(3):214-5.

5 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. [email protected]

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.