RGD Reference Report - A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy. - Rat Genome Database

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A sensitized mutagenesis screen identifies Gli3 as a modifier of Sox10 neurocristopathy.

Authors: Matera, Ivana  Watkins-Chow, Dawn E  Loftus, Stacie K  Hou, Ling  Incao, Arturo  Silver, Debra L  Rivas, Cecelia  Elliott, Eugene C  Baxter, Laura L  Pavan, William J 
Citation: Matera I, etal., Hum Mol Genet. 2008 Jul 15;17(14):2118-31. doi: 10.1093/hmg/ddn110. Epub 2008 Apr 7.
RGD ID: 12738207
Pubmed: PMID:18397875   (View Abstract at PubMed)
PMCID: PMC2902284   (View Article at PubMed Central)
DOI: DOI:10.1093/hmg/ddn110   (Journal Full-text)

Haploinsufficiency for the transcription factor SOX10 is associated with the pigmentary deficiencies of Waardenburg syndrome (WS) and is modeled in Sox10 haploinsufficient mice (Sox10(LacZ/+)). As genetic background affects WS severity in both humans and mice, we established an N-ethyl-N-nitrosourea (ENU) mutagenesis screen to identify modifiers that increase the phenotypic severity of Sox10(LacZ/+) mice. Analysis of 230 pedigrees identified three modifiers, named modifier of Sox10 neurocristopathies (Mos1, Mos2 and Mos3). Linkage analysis confirmed their locations on mouse chromosomes 13, 4 and 3, respectively, within regions distinct from previously identified WS loci. Positional candidate analysis of Mos1 identified a truncation mutation in a hedgehog(HH)-signaling mediator, GLI-Kruppel family member 3 (Gli3). Complementation tests using a second allele of Gli3 (Gli3(Xt-J)) confirmed that a null mutation of Gli3 causes the increased hypopigmentation in Sox10(LacZ/+);Gli3(Mos1/)(+) double heterozygotes. Early melanoblast markers (Mitf, Sox10, Dct, and Si) are reduced in Gli3(Mos1/)(Mos1) embryos, indicating that loss of GLI3 signaling disrupts melanoblast specification. In contrast, mice expressing only the GLI3 repressor have normal melanoblast specification, indicating that the full-length GLI3 activator is not required for specification of neural crest to the melanocyte lineage. This study demonstrates the feasibility of sensitized screens to identify disease modifier loci and implicates GLI3 and other HH signaling components as modifiers of human neurocristopathies.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
piebaldism  ISOGli3 (Mus musculus)12738207; 12738207 RGD 
piebaldism  IMP 12738207 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Gli3  (GLI family zinc finger 3)

Genes (Mus musculus)
Gli3  (GLI-Kruppel family member GLI3)

Genes (Homo sapiens)
GLI3  (GLI family zinc finger 3)


Additional Information