PAX3 gene structure and mutations: close analogies between Waardenburg syndrome and the Splotch mouse

Abstract

The human PAX3 gene contains a paired box and a paired-type homeobox, and is believed to play a role in pattern formation in the embryo. We describe the exon-intron structure of the homeobox-containing part of PAX3, complementing earlier descriptions of the 5' part of the gene. Mutations in PAX3 have been described in patients with Type 1 Waardenburg syndrome, who have hearing loss and pigmentary abnormalities, while Splotch mice have mutations in the homologous mouse Pax-3 gene. We describe a series of patients who have previously unidentified PAX3 mutations. These include a chromosomal deletion, a splice-site mutation and an amino acid substitution which closely correspond to the molecular changes seen in the Splotch-retarded, Splotch and Splotch-delayed mouse mutants respectively. These mutations confirm that Waardenburg syndrome is produced by gene dosage effects and show that the phenotypic differences between Splotch mice and humans with Waardenburg syndrome are caused by differences in genetic background rather than different primary effects of the mutations.

Cell-type-specific regulation of distinct sets of gene targets by Pax3 and Pax3/FKHR

“…Mutations in PAX3 in humans gives rise to Waardenburg syndrome (Hoth et al, 1993;Baldwin et al, 1994), which is characterized by pigmentation, craniofacial, limb and hearing defects. Genetic analysis of splotch (sp) mice (Tassabehji et al, 1994), which harbour a null mutation in Pax3, further revealed a role for this transcription factor in the development of the neural tube, peripheral nervous system (Tremblay et al, 1995) and limb musculature (Bober et al, 1994;Epstein et al, 1996;Conway et al, 1997b), as well as in a number of tissues, which require specific migrating neural crest cell populations including the heart and the dermis (Conway et al, 1997a).…”

Application of Mouse Models to Research in Hearing and Balance

“…1n 1992, Friedman and Ryan had published an influential review on transgenic mice (Friedman and Ryan 1992), and the first characterizations began to appear (Rauch 1992). It was around this time that the first mouse orthologs of human deafness genes were identified (Birkenmeier et al 1989;Steel and Smith 1992;Hughes et al 1994;Tassabehji et al 1994;Battinelli et al 1996) and mouse deafness genes were first tied to proteins critical for hearing (Avraham et al 1995;Gibson et al 1995). Prior to 1999, most mouse studies applied Bforward genetics,^whereby useful defects are identified in existing mouse stocks.…”

An Engineered PAX3-KRAB Transcriptional Repressor Inhibits the Malignant Phenotype of Alveolar Rhabdomyosarcoma Cells Harboring the Endogenous PAX3-FKHR Oncogene

“…For PAX3, this view is based on analysis of embryonic expression patterns and the developmental defect syndromes associated with specific mutations: the splotch mouse and the human Waardenburg syndrome (12,72). Pax-3 and Pax-7 exhibit partially overlapping patterns of early expression in developing mouse central nervous system and during formation of dermomyotome and limb bud mesenchyme (50,67).…”