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.

Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival

“…Along these lines, serine 298 of MITF, a GSK3b phosphoacceptor site, was found to be mutated to proline in a WS type 2 patient (Tassabehji et al, 1995;Takeda et al, 2000a). Absence of this serine abrogated DNA binding and transcriptional activity of MITF on the tyrosinase model promoter in vitro.…”

PAX3: A Molecule with Oncogenic or Tumor Suppressor Function Is Involved in Cancer

“…Specific mutations within a number of PAX/ Pax (human/mouse) genes lead to a range of developmental abnormalities in both human beings and mouse. Many studies proved that PAX3 loss of function mutations are involved in either type 1 or type 3 Waardenburg syndrome [59][60][61][62][63][64][65]. PAX3/Pax3 (human/mouse) mutations are associated with limb muscle hypoplasia in Waardenburg syndrome patients and Splotch phenotype mice, respectively [54,55].…”

“…Interestingly, PAX3 mutations were typically not found in families with other neurocristopathies [64]. Mutations that partially abolish the activity of PAX2, PAX3, and PAX6 were known to cause dysmorphic syndromes with developmental abnormalities [66][67][68][69][70].…”

A Comparative Study of Eya1 and Eya4 Protein Function and Its Implication in Branchio-oto-renal Syndrome and DFNA10

“…Particularly vulnerable to haploinsufficiency are regulatory genes working close to threshold levels in specific tissues. Examples include PAX3, which is responsible for Waardenburg syndrome Type 1 (Tassabehji et al 1995), and SOX9, a cause of campomelic dysplasia (Sock et al 2001). Based on our data, EYA1 and EYA4 can be added to this list.…”