Review and update of mutations causing Waardenburg syndrome

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.

Development of the stria vascularis and potassium regulation in the human fetal cochlea: Insights into hereditary sensorineural hearing loss

“…Its four subtypes are based on clinical symptoms and multiple causative genes have been identified (Pingault et al, 2010). We show here that in the human fetal cochlea, MITF expression is confined to melanocytes [Fig.…”

“…Examples of syndromic SNHL include Pendred's syndrome ([MIM 274600, www.omim.org/], combining hearing loss and goiter (Pendred, 1896; Bizhanova and Kopp, 2010)), Waardenburg syndrome [WS; hearing loss and pigmentation abnormalities (Waardenburg, 1951; Pingault et al, 2010)] and Jervell and Lange‐Nielsen syndrome ([MIM 220400 and MIM 612347], hearing loss and cardiac symptoms (Jervell and Lange‐Nielsen, 1957)). In nonsyndromic SNHL, associations with obvious abnormalities of the external ear or symptoms other than hearing loss cannot be found, but the heterogeneity of loci and genes is high: over 130 loci have been mapped and over 60 different genes have been implicated presently (van Camp and Smith).…”

Organ of Corti and Stria Vascularis: Is there an Interdependence for Survival?

“…Loss of melanocytes due to Mitf mutation causes abnormality of the stria morphology and function, leading to hearing loss in both humans and mice [16,21,22]. Mitf mutation in humans is one of the causes of Waardenburg syndrome [23], a group of genetic conditions that can cause hearing loss and change in coloring of the hair, skin, and eyes [24]. We used this mouse model to determine whether a change in the electrochemical environment (i.e., reduction of EP) in the endolymph maintained by the stria would affect function and survival of hair cells.…”

Spectrum of Temporal Bone Abnormalities in Patients with Waardenburg Syndrome andSOX10Mutations

“…1 Four distinct subtypes have been described since then, all characterized by deafness and pigmentary disturbance (for review, see Pingault et al 2 ). WS has an incidence of approximately 1/40,000 births and is responsible for 1%-3% of cases of congenital deafness.…”

“…10 Because none of these studies included mo-lecular analyses, however, these inner ear malformations have not been linked to a particular molecular defect. WS is clinically and genetically heterogeneous (for a review see Pingault et al 2 ). Several genes are involved (PAX3, MITF, EDN3, EDNRB, SOX10), with SOX10 mutations causing approximately 15% of type 2 WS, which is distinguished from type 1 WS by the absence of dystopia canthorum, and Ͼ50% of type 4 WS, which is also known as WS2 ϩ Hirschsprung disease or chronic intestinal pseudoobstruction.…”