A mouse model of Waardenburg syndrome type 4 with a new spontaneous mutation of the endothelin-B receptor gene

Yoshibumi Matsushima, Yusuke Shinkai, Yasuhito Kobayashi, Michihiro Sakamoto, Tetsuo Kunieda, Masayoshi Tachibana

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Waardenburg syndrome (WS) is a hereditary auditory-pigmentary syndrome with hearing impairment and pigmentation anomaly of the skin and iris. In addition to these major symptoms, WS type 4 is associated with Hirschsprung disease. To date, three genes responsible for WS4 have been cloned: genes for a transcription factor SOX10, endothelin 3 (EDN3), and endothelin B receptor (EDNRB). We here describe a novel mutant mouse with a mutation of the Ednrb gene, and propose the mouse as an animal model of WS4. These mutants are with mixed genetic background of BALB/c and MSM (an inbred strain of Japanese wild mice) and have extensive white spotting. They died between 2 and 7 weeks after birth owing to megacolon: their colon distal to the megacolon lacked Auerbach's plexus cells. Interestingly, these mutants did not respond to sound, and the stria vascularis of their cochlea lacked intermediate cells, i.e., neural crest-derived melanocytes. Since these symptoms resembled those of human WS4 and were transmitted in autosomal recessive hereditary manner, the mutants were named WS4 mice. Breeding analysis revealed that WS4 mice are allelic with piebald-lethal and JF1 mice, which are also mutated in the Ednrb gene. Mutation analysis revealed that their Ednrb lacked 318 nucleotides encoding Ednrb transmembrane domains owing to deletion of exons 2 and 3. Interaction between endothelin 3 and its receptor is required for normal differentiation and development of melanocytes and Auerbach's plexus cells. We concluded that a missing interaction here led to a lack of these cells, which caused pigmentation anomaly, deafness, and megacolon in WS4 mice.

Original languageEnglish
Pages (from-to)30-35
Number of pages6
JournalMammalian Genome
Volume13
Issue number1
DOIs
Publication statusPublished - 2002

Fingerprint

Endothelin B Receptors
Megacolon
Mutation
Genes
Myenteric Plexus
Melanocytes
SOXE Transcription Factors
Waardenburg Syndrome
Endothelin-3
Stria Vascularis
Skin Pigmentation
Hirschsprung Disease
Metrorrhagia
Neural Crest
Cochlea
Pigmentation
Deafness
Iris
Type 4 Waardenburg syndrome
Hearing Loss

ASJC Scopus subject areas

  • Genetics

Cite this

A mouse model of Waardenburg syndrome type 4 with a new spontaneous mutation of the endothelin-B receptor gene. / Matsushima, Yoshibumi; Shinkai, Yusuke; Kobayashi, Yasuhito; Sakamoto, Michihiro; Kunieda, Tetsuo; Tachibana, Masayoshi.

In: Mammalian Genome, Vol. 13, No. 1, 2002, p. 30-35.

Research output: Contribution to journalArticle

Matsushima, Yoshibumi ; Shinkai, Yusuke ; Kobayashi, Yasuhito ; Sakamoto, Michihiro ; Kunieda, Tetsuo ; Tachibana, Masayoshi. / A mouse model of Waardenburg syndrome type 4 with a new spontaneous mutation of the endothelin-B receptor gene. In: Mammalian Genome. 2002 ; Vol. 13, No. 1. pp. 30-35.
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