Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease

Mutation of the Sry-related Sox10 gene in Dominant megacolon, a mouse model for human Hirschsprung disease

^*Zentrum für Molekulare Neurobiologie, Universität Hamburg, 20246 Hamburg, Germany; and ^‡Institut National de la Santé et de la Recherche Médicale, U468, Hôpital Henri Mondor, 94010 Créteil, France

Communicated by Yuet Wai Kan, University of California, San Francisco, CA (received for review January 2, 1998)

Abstract

The spontaneous mouse mutant Dominant megacolon (Dom) is a valuable model for the study of human congenital megacolon (Hirschsprung disease). Here we report that the defect in the Dom mouse is caused by mutation of the gene encoding the Sry-related transcription factor Sox10. This assignment is based on (i) colocalization of the Sox10 gene with the Dom mutation on chromosome 15; (ii) altered Sox10 expression in the gut and in neural-crest derived structures of cranial ganglia of Dom mice; (iii) presence of a frameshift in the Sox10 coding region, and (iv) functional inactivation of the resulting truncated protein. These results identify the transcriptional regulator Sox10 as an essential factor in mouse neural crest development and as a further candidate gene for human Hirschsprung disease, especially in cases where it is associated with features of Waardenburg syndrome.

Footnotes

↵ † B.H. and V.P. contributed equally to this work and should both be considered first authors.
↵ § Present address: Laboratorio di Genetica Molecolare, Istituto G. Gaslini, 16148 Genoa, Italy.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AF047043 and AF047389).
¶ To whom reprint requests should be addressed. e-mail: wegner{at}plexus.uke.uni-hamburg.de.
ABBREVIATIONS:

E,

embryonic day;

ENS,

enteric nervous system;

HMG,

high-mobility group;

YAC,

yeast artificial chromosome;

NF,

neurofilament protein