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Vol. 9, Issue 3, 215-225, March 1999
The Sox10Dom Mouse: Modeling the Genetic Variation of Waardenburg-Shah (WS4) Syndrome
E. Michelle
Southard-Smith,1
Misha
Angrist,2
Jane S.
Ellison,1
Richa
Agarwala,1
Andreas D.
Baxevanis,3
Aravinda
Chakravarti,2 and
William J.
Pavan1,4
1 Genetic Disease Research Branch, National Human Genome
Research Institute, National Institutes of Health (NIH), Bethesda,
Maryland 20892-4472 USA; 2 Department of Genetics and Center
for Human Genetics, Case Western Reserve University and University
Hospitals of Cleveland, Cleveland, Ohio 44106-4955 USA;
3 Genome Technology Branch, National Human Genome Research
Institute, National Institutes of Health,
Bethesda, Maryland 20892-4431 USA
Hirschsprung disease (HSCR) is a multigenic neurocristopathy
clinically recognized by aganglionosis of the distal gastrointestinal tract. Patients presenting with aganglionosis in association with hypopigmentation are classified as Waardenburg syndrome type 4 (Waardenburg-Shah, WS4). Variability in the disease phenotype of WS4
patients with equivalent mutations suggests the influence of genetic
modifier loci in this disorder. Sox10Dom/+ mice
exhibit variability of aganglionosis and hypopigmentation influenced by
genetic background similar to that observed in WS4 patients. We have
constructed Sox10Dom/+ congenic lines to segregate
loci that modify the neural crest defects in these mice. Consistent
with previous studies, increased lethality of
Sox10Dom/+ animals resulted from a C57BL/6J
locus(i). However, we also observed an increase in hypopigmentation in
conjunction with a C3HeB/FeJLe-a/a locus(i). Linkage analysis localized
a hypopigmentation modifier of the Dom phenotype to mouse
chromosome 10 in close proximity to a previously reported modifier of
hypopigmentation for the endothelin receptor B mouse model of WS4. To
evaluate further the role of SOX10 in development and disease,
we have performed comparative genomic analyses. An essential role for this gene in neural crest development is supported by zoo blot hybridizations that reveal extensive conservation throughout vertebrate evolution and by similar Northern blot expression profiles between mouse and man. Comparative sequence analysis of the mouse and human
SOX10 gene have defined the exon-intron boundaries of
SOX10 and facilitated mutation analysis leading to the
identification of two new SOX10 mutations in individuals with WS4.
Structural analysis of the HMG DNA-binding domain was performed to
evaluate the effect of human mutations in this region.
4
Corresponding author.
9:215-225 ©1999 by Cold Spring Harbor Laboratory Press ISSN 1088-9051/99 $5.00
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