title: The mutational spectrum in Waardenburg syndrome.
abstract: One hundred and thirty-four families or individuals with auditory-pigmentary syndromes such as Waardenburg syndrome (WS) or probable neurocristopathies were screened for mutations in the PAX3 and MITF genes. PAX3 mutations were found in 20/25 families with definite Type 1 WS and 1/2 with Type 3 WS, but in none of 23 with definite Type 2 WS or 36 with other neurocristopathies. The PAX3 mutations included substitutions of conserved amino acids in the paired domain or the homeodomain, splice-site mutations, nonsense mutations and frame-shifting insertions or deletions. No phenotype-genotype correlations were noted within WS1 families. With MITF, mutations likely to affect protein function were found in seven families, five of which had definite Type 2 WS. We conclude that Type 1 and Type 3 WS are allelic and are normally caused by loss of function mutations in PAX3; that Type 2 WS is heterogeneous, with about 20% of cases caused by mutations in MITF, and that individuals with auditory, pigmentary or neural crest syndromes which do not fit stringent definitions of Waardenburg syndrome are unlikely to have mutations in either the PAX3 or MITF genes. The molecular pathology of MITF/microphthalmia mutations appears to be different in humans and mice, with gene dosage having more significant effects in humans than in the mouse.
authors.affiliation: Department of Medical Genetics, St Mary's Hospital, Manchester, UK.
authors.forename: M
authors.initials: M
authors.lastname: Tassabehji
authors.forename: V E
authors.initials: VE
authors.lastname: Newton
authors.forename: X Z
authors.initials: XZ
authors.lastname: Liu
authors.forename: A
authors.initials: A
authors.lastname: Brady
authors.forename: D
authors.initials: D
authors.lastname: Donnai
authors.forename: M
authors.initials: M
authors.lastname: Krajewska-Walasek
authors.forename: V
authors.initials: V
authors.lastname: Murday
authors.forename: A
authors.initials: A
authors.lastname: Norman
authors.forename: E
authors.initials: E
authors.lastname: Obersztyn
authors.forename: W
authors.initials: W
authors.lastname: Reardon
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000235:genetics*; D006801:Humans; D051739:Microphthalmia-Associated Transcription Factor; D008969:Molecular Sequence Data; D009154:Mutation; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; D014849:Waardenburg Syndrome / Q000235:genetics*
chemical_list: D017931:DNA Primers; D004268:DNA-Binding Proteins; C497234:MITF protein, human; D051739:Microphthalmia-Associated Transcription Factor; D000072041:PAX3 Transcription Factor; C489409:PAX3 protein, human; D051761:Paired Box Transcription Factors; D014157:Transcription Factors; C068686:Pax3 protein, mouse