Homozygous and heterozygous inheritance of <i>PAX3</i> mutations causes different types of Waardenburg syndrome

Wollnik, Bernd; Tükel, Turgut; Uyguner, Zehra Oya; Ghanbari, Asadollah; Kayserili, Hülya; Emiroglu, M; Yüksel‐Apak, Memnune

doi:10.1002/ajmg.a.20260

Cited by 77 publications

(50 citation statements)

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“…On occasion, missense or specific deletion mutations in the paired domain of the PAX3 gene can cause WS-III (Fig. 4 B) (Wollnik et al, 2003). Thus, additional analyses of the 22-1 phenotype will contribute further to our understanding of PAX3 structure and function in humans (Engelkamp and van Heyningen, 1996;Fortin et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

“…The Shh signaling pathway has been shown to play essential roles in the anterior CNS patterning (Hooper and Scott, 2005), neuronal development (Roelink et al, 1994;Ericson et al, 1995), and guidance within the ventral neural tube (Charron et al, Vogan et al, 1993;Zlotogora et al, 1995;Fortin et al, 1997;Sotirova et al, 2000;Wollnik et al, 2003). Figure 5.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, mutations that cause amino acid substitutions in the paired box of the human PAX3 protein have been associated with the auditory-pigmentary type I Waardenburg syndrome (WS-I) (Fig. 4 B) (Zlotogora et al, 1995;Fortin et al, 1997;Sotirova et al, 2000;Wollnik et al, 2003).…”

Section: Identification Of a Mutation With Abnormal Sensory Ganglia Dmentioning

confidence: 99%

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A Genetic Screen for Mutations That Affect Cranial Nerve Development in the Mouse

Mar

Rivkin²,

Kim³

et al. 2005

J. Neurosci.

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Cranial motor and sensory nerves arise stereotypically in the embryonic hindbrain, act as sensitive indicators of general and regionspecific neuronal development, and are directly or indirectly affected in many human disorders, particularly craniofacial syndromes. The molecular genetic hierarchies that regulate cranial nerve development are mostly unknown. Here, we describe the first mouse genetic screen that has used direct immunohistochemical visualization methods to systematically identify genetic loci required for cranial nerve development. After screening 40 pedigrees, we recovered seven new neurodevelopmental mutations. Two mutations model human genetic syndromes. Mutation 7-1 causes facial nerve anomalies and a reduced lower jaw, and is located in a region of conserved synteny with an interval associated with the micrognathia and mental retardation of human cri-du-chat syndrome. Mutation 22-1 is in the Pax3 gene and, thus, models human Waardenburg syndrome. Three mutations cause global axon guidance deficits: one interferes with initial motor axon extension from the neural tube, another causes overall axon defasciculation, and the third affects general choice point selection. Another two mutations affect the oculomotor nerve specifically. Oculomotor nerve development, which is disrupted by six mutations, appears particularly sensitive to genetic perturbations. Phenotypic comparisons of these mutants identifies a "transition zone" that oculomotor axons enter after initial outgrowth and in which new factors govern additional progress. The number of interesting neurodevelopmental mutants revealed by this small-scale screen underscores the promise of similar focused genetic screens to contribute significantly to our understanding of cranial nerve development and human craniofacial syndromes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A Genetic Screen for Mutations That Affect Cranial Nerve Development in the Mouse

Mar

Rivkin²,

Kim³

et al. 2005

J. Neurosci.

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“…Pigmentary abnormalities of the hair, skin and eyes; congenital sensorineural hearing loss; dystopia canthorum; lateral displacement of the ocular inner canthi and upper limb abnormalities Hoth et al, 1993;Zlotogora, 1995;Tekin et al, 2001;Wollnik et al, 2003 'Splotch'/mouse A-to-T transversion of the AG splice acceptor of intron 3 of Pax3 uncertainty about Pax3 requirement for NC migration (Li et al, 1999;Conway et al, 2000;Kwang et al, 2002;Chan et al, 2004) has been addressed recently by looking at the role of Pax3 in migratory cardiac NC cells using the Pax3 mutant Splotch mouse models, all six of which have different mutations in Pax3 (Table 2). In all Splotch mice, cardiac NC cells fail to undergo proliferative expansion prior to migration due to defects intrinsic to the NC cell.…”

Section: Heterogeneous Mutations In Pax3mentioning

confidence: 99%

Pax genes: regulators of lineage specification and progenitor cell maintenance

2014

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Pax genes encode a family of transcription factors that orchestrate complex processes of lineage determination in the developing embryo. Their key role is to specify and maintain progenitor cells through use of complex molecular mechanisms such as alternate RNA splice forms and gene activation or inhibition in conjunction with protein co-factors. The significance of Pax genes in development is highlighted by abnormalities that arise from the expression of mutant Pax genes. Here, we review the molecular functions of Pax genes during development and detail the regulatory mechanisms by which they specify and maintain progenitor cells across various tissue lineages. We also discuss mechanistic insights into the roles of Pax genes in regeneration and in adult diseases, including cancer. KEY WORDS: Pax genes, Embryogenesis, Lineage determination IntroductionPaired box (Pax) genes encode transcription factors that contain a highly conserved DNA-binding domain called the paired domain (PD, Fig. 1A) and can be considered to be a principle regulator of gene expression. Nine Pax genes (Pax1-Pax9) have been characterised in mammals and the evolutionary conserved paired domain has been identified across phylogenies from insects, to amphibians and birds. In higher vertebrates, PAX proteins are subclassified into groups according to inclusion of an additional DNA-binding homeodomain and/or an octapeptide region, which serves as a binding motif for protein co-factors for potent inhibition of downstream gene transcription (Eberhard et al., 2000) (Fig. 1B); all PAX proteins include a transactivation domain located within the C-terminal amino acids (Underhill, 2012). It is also known that all Pax genes, with the exception of Pax4 and Pax9, produce alternative RNA transcripts (see Table 1). The functional diversity of Pax proteins in vivo is thus linked to the ability to produce alternatively spliced gene products that differ in structure and, consequently, in the binding activity of their paired and homeodomain DNA-binding regions (Underhill, 2012).Three decades ago, the characterisation and roles of Pax genes in embryonic development began to unfold. Early studies discovered that regulatory gene families such as the Pax family are involved in the sequential compartmentalisation and body patterning of developing organisms; thereafter, studies highlighted a role for Pax genes in the early specification of cell fate and the subsequent morphogenesis of various tissues and organs. Following this, mutational studies of Pax genes confirmed the importance of these regulatory roles in the PRIMER School of Medical Sciences, Edith Cowan University, Joondalup, WA 6027, Australia.*Author for correspondence (j.blake@ecu.edu.au) This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.initiation and progression of ...

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“…The disease is thought to be fully penetrant when considering at least one sign, but the penetrance of each feature is not complete. Homozygous or compound heterozygous PAX3 mutations have been described in severe cases of WS3, with extended depigmentation and upper limb defects, sometimes leading to death in early infancy or in utero [Bottani et al, 1999;Wollnik et al, 2003;Zlotogora et al, 1995]. In the last two cases, heterozygous relatives present with WS1.…”

Section: Clinical Features and Classificationmentioning

confidence: 99%

Review and update of mutations causing Waardenburg syndrome

et al. 2010

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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.

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Homozygous and heterozygous inheritance of PAX3 mutations causes different types of Waardenburg syndrome

Cited by 77 publications

References 19 publications

A Genetic Screen for Mutations That Affect Cranial Nerve Development in the Mouse

A Genetic Screen for Mutations That Affect Cranial Nerve Development in the Mouse

Pax genes: regulators of lineage specification and progenitor cell maintenance

Review and update of mutations causing Waardenburg syndrome

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