Article

Molecular basis of splotch and Waardenburg PAX-3 mutations

Max-Planck-Institute for Biophysical Chemistry, Department of Molecular Cell Biology, Göttingen, Federal Republic of Germany.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 05/1994; 91(9):3685-9. DOI: 10.1073/pnas.91.9.3685
Source: PubMed

ABSTRACT Pax genes control certain aspects of development, as mutations result in (semi)dominant defects apparent during embryogenesis. Pax-3 has been associated with the mouse mutant splotch (Sp) and the human Waardenburg syndrome type 1 (WS1). We have examined the molecular basis of splotch and WS1 by studying the effect of mutations on DNA binding, using a defined target sequence. Pax-3 contains two different types of functional DNA-binding domains, a paired domain and a homeodomain. Mutational analysis of Pax-3 reveals different modes of DNA binding depending on the presence of these domains. A segment of Pax-3 located between the two DNA-binding domains, including a conserved octapeptide, participates in protein homodimerization. Pax-3 mutations found in splotch alleles and WS1 individuals change DNA binding and, in the case of a protein product of the Sp allele, dimerization. These findings were taken as a basis to define the molecular nature of the mutants.

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    • "To distinguish between these hypotheses, mice were bred to introduce the Pax3 Sp or Pax3 Sp-d mutant alleles into the Wnt1-Cre; Foxd3 flox/− background (Supplementary Fig. 1). Pax3 Sp is a null allele encoding a truncated Pax3 protein (Chalepakis et al., 1994). "
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    ABSTRACT: The transcription factors Foxd3 and Pax3 are important early regulators of neural crest (NC) progenitor cell properties. Homozygous mutations of Pax3 or a homozygous NC-specific deletion of Foxd3 cause marked defects in most NC derivatives, but neither loss of both Foxd3 alleles nor loss of one Pax3 allele alone greatly affects overall development of cardiac NC derivatives. In contrast, compound mutant embryos homozygous for a NC-specific Foxd3 mutation and heterozygous for Pax3 have fully penetrant persistent truncus arteriosus, severe thymus hypoplasia, and midgestation lethality. Foxd3; Pax3 compound mutant embryos have increased cell death in the neural folds and a drastic early reduction of NC cells, with an almost complete absence of NC caudal to the first pharyngeal arch. The genetic interaction between these genes implicates gene dosage-sensitive roles for Foxd3 and Pax3 in cardiac NC progenitors. Foxd3 and Pax3 act together to affect survival and maintenance of cardiac NC progenitors, and loss of these progenitors catastrophically affects key aspects of later cardiovascular development.
    genesis 01/2011; 49(1):10-23. DOI:10.1002/dvg.20686 · 2.04 Impact Factor
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    • "A few mutations have been tested for their functional consequences. The tests mostly included DNA-binding activity and transactivation capabilities [Chalepakis et al., 1994; Corry and Underhill, 2005; Fortin et al., 1997; Watanabe et al., 1998]. "
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    ABSTRACT: Waardenburg syndrome (WS) is characterized by the association of pigmentation abnormalities, including depigmented patches of the skin and hair, vivid blue eyes or heterochromia irides, and sensorineural hearing loss. However, other features such as dystopia canthorum, musculoskeletal abnormalities of the limbs, Hirschsprung disease, or neurological defects are found in subsets of patients and used for the clinical classification of WS. Six genes are involved in this syndrome: PAX3 (encoding the paired box 3 transcription factor), MITF (microphthalmia-associated transcription factor), EDN3 (endothelin 3), EDNRB (endothelin receptor type B), SOX10 (encoding the Sry bOX10 transcription factor), and SNAI2 (snail homolog 2), with different frequencies. In this review we provide an update on all WS genes and set up mutation databases, summarize molecular and functional data available for each of them, and discuss the applications in diagnostics and genetic counseling. Hum Mutat 31, 1–16, 2010. © 2010 Wiley-Liss, Inc.
    Human Mutation 04/2010; 31(4):391 - 406. DOI:10.1002/humu.21211 · 5.05 Impact Factor
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    • "In humans, heterozygous mutations in PAX3 are found in Waardenburg syndromes types I and III (Baldwin et al., 1995; Chalepakis et al., 1994; Tassabehji et al., 1992), features of which include a characteristic pigmentation defect analogous to the belly spot, or occasional white head patch (of splotch mice), and sensorineural deafness and characteristic facial appearance (reviewed by Machado et al., 2001a). Although NTDs are not a major feature, spina bifida has been reported in patients with Waardenburg syndrome (Carezani-Gavin et al., 1992; Chatkupt and Johnson, 1993), and exencephaly was found in a suspected homozygous case (Aymé and Philip , 1995). "
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    ABSTRACT: Splotch mutant mice develop neural tube defects (NTDs), comprising exencephaly and/or spina bifida, as well as neural crest-related defects and abnormalities of limb musculature. Defects in splotch mice result from mutations in Pax3, and some human NTDs may also result from mutations in the human PAX3 gene. Pax3 encodes a transcription factor whose function may influence expression of multiple downstream genes associated with a variety of cellular properties (including apoptosis, adhesion, proliferation, and differentiation), that could be important for neural tube closure. The frequency of NTDs varies between mutant alleles and is also influenced by genetic background and environmental factors. Notably, splotch provides a model for folic acid-preventable NTDs, and conversely, dietary folate deficiency exacerbates NTDs. Understanding the molecular and cellular basis of splotch NTDs, as well as the mechanisms by which the frequency of defects is influenced by genetic and environmental factors (such as sub-optimal folate status), may provide insight into the causation of these severe congenital malformations in humans.
    Birth Defects Research Part A Clinical and Molecular Teratology 04/2009; 85(4):322-30. DOI:10.1002/bdra.20539 · 2.21 Impact Factor
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