Disrupted SOX10 function causes spongiform neurodegeneration in gray tremor mice.

[hirschsprung disease]

Mice homozygous for the gray tremor (gt ) mutation have a pleiotropic phenotype that includes pigmentation defects , megacolon , whole body tremors , sporadic seizures , hypo- and dys-myelination of the central nervous system (CNS ) and peripheral nervous system , vacuolation of the CNS , and early death . Vacuolation similar to that caused by prions was originally reported to be transmissible , but subsequent studies showed the inherited disease was not infectious . The gt mutation mapped to distal mouse chromosome 15 , to the same region as Sox 10 , which encodes a transcription factor with essential roles in neural crest survival and differentiation . As dominant mutations in mouse or human SOX 10 cause white spotting and intestinal aganglionosis , we screened the Sox 10 coding region for mutations in gt /gt DNA . An adenosine to guanine transversion was identified in exon 2 that changes a highly conserved glutamic acid residue in the SOX 10 DNA binding domain to glycine . This mutant allele was not seen in wildtype mice , including the related GT /Le strain , and failed to complement a Sox 10 null allele . Gene expression analysis revealed significant down-regulation of genes involved in myelin lipid biosynthesis pathways in gt /gt brains . Knockout mice for some of these genes develop CNS vacuolation and /or myelination defects , suggesting that their down-regulation may contribute to these phenotypes in gt mutants and could underlie the neurological phenotypes associated with peripheral demyelinating neuropathy -central dysmyelinating leukodystrophy -Waardenburg syndrome -Hirschsprung disease , caused by mutations in human SOX 10 .

Diseases
Validation

Diseases presenting "neuropathy" symptom

adrenomyeloneuropathy

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

fabry disease

focal myositis

gm1 gangliosidosis

hirschsprung disease

homocystinuria without methylmalonic aciduria

inclusion body myositis

krabbe disease

malignant atrophic papulosis

megacystis-microcolon-intestinal hypoperistalsis syndrome

neuralgic amyotrophy

oculocutaneous albinism

pendred syndrome

phenylketonuria

pyomyositis

pyruvate dehydrogenase deficiency

sneddon syndrome

thoracic outlet syndrome

triple a syndrome

von hippel-lindau disease

waldenström macroglobulinemia

wolf-hirschhorn syndrome

This symptom has already been validated