Document Detail

Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis.
MedLine Citation:
PMID:  19079258     Owner:  NLM     Status:  MEDLINE    
Abnormalities in WNT signaling are implicated in a broad range of developmental anomalies and also in tumorigenesis. Here we demonstrate that germline mutations in WTX (FAM123B), a gene that encodes a repressor of canonical WNT signaling, cause an X-linked sclerosing bone dysplasia, osteopathia striata congenita with cranial sclerosis (OSCS; MIM300373). This condition is typically characterized by increased bone density and craniofacial malformations in females and lethality in males. The mouse homolog of WTX is expressed in the fetal skeleton, and alternative splicing implicates plasma membrane localization of WTX as a factor associated with survival in males with OSCS. WTX has also been shown to be somatically inactivated in 11-29% of cases of Wilms tumor. Despite being germline for such mutations, individuals with OSCS are not predisposed to tumor development. The observed phenotypic discordance dependent upon whether a mutation is germline or occurs somatically suggests the existence of temporal or spatial constraints on the action of WTX during tumorigenesis.
Zandra A Jenkins; Margriet van Kogelenberg; Tim Morgan; Aaron Jeffs; Ryuji Fukuzawa; Esther Pearl; Christina Thaller; Anne V Hing; Mary E Porteous; Sixto Garcia-Miñaur; Axel Bohring; Didier Lacombe; Fiona Stewart; Torunn Fiskerstrand; Laurence Bindoff; Siren Berland; Lesley C Adès; Michel Tchan; Albert David; Louise C Wilson; Raoul C M Hennekam; Dian Donnai; Sahar Mansour; Valérie Cormier-Daire; Stephen P Robertson
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-12-14
Journal Detail:
Title:  Nature genetics     Volume:  41     ISSN:  1546-1718     ISO Abbreviation:  Nat. Genet.     Publication Date:  2009 Jan 
Date Detail:
Created Date:  2008-12-29     Completed Date:  2009-01-23     Revised Date:  2013-06-18    
Medline Journal Info:
Nlm Unique ID:  9216904     Medline TA:  Nat Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  95-100     Citation Subset:  IM    
Departments of Paediatrics, Dunedin School of Medicine, Otago University, Dunedin 9054, New Zealand.
Data Bank Information
Bank Name/Acc. No.:
OMIM/MIM300373; RefSeq/NM_175179
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MeSH Terms
Adaptor Proteins, Signal Transducing
Alternative Splicing / genetics
Bone Diseases, Developmental / complications,  genetics*,  pathology*
Child, Preschool
Chromosome Deletion
Chromosomes, Human, Pair 11 / genetics
Embryo, Mammalian / metabolism
Genetic Predisposition to Disease*
Germ-Line Mutation / genetics*
Middle Aged
Point Mutation
Precancerous Conditions / genetics*
Protein Structure, Tertiary
Tumor Suppressor Proteins / chemistry,  genetics*
Wilms Tumor / genetics
X Chromosome Inactivation / genetics
Reg. No./Substance:
0/AMER1 protein, human; 0/Adaptor Proteins, Signal Transducing; 0/Tumor Suppressor Proteins

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