title: Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis.
abstract: 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.
authors.affiliation: Departments of Paediatrics, Dunedin School of Medicine, Otago University, Dunedin 9054, New Zealand.
authors.forename: Zandra A
authors.initials: ZA
authors.lastname: Jenkins
authors.forename: Margriet
authors.initials: M
authors.lastname: van Kogelenberg
authors.forename: Tim
authors.initials: T
authors.lastname: Morgan
authors.forename: Aaron
authors.initials: A
authors.lastname: Jeffs
authors.forename: Ryuji
authors.initials: R
authors.lastname: Fukuzawa
authors.forename: Esther
authors.initials: E
authors.lastname: Pearl
authors.forename: Christina
authors.initials: C
authors.lastname: Thaller
authors.forename: Anne V
authors.initials: AV
authors.lastname: Hing
authors.forename: Mary E
authors.initials: ME
authors.lastname: Porteous
authors.forename: Sixto
authors.initials: S
authors.lastname: Garcia-Miñaur
authors.forename: Axel
authors.initials: A
authors.lastname: Bohring
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: Fiona
authors.initials: F
authors.lastname: Stewart
authors.forename: Torunn
authors.initials: T
authors.lastname: Fiskerstrand
authors.forename: Laurence
authors.initials: L
authors.lastname: Bindoff
authors.forename: Siren
authors.initials: S
authors.lastname: Berland
authors.forename: Lesley C
authors.initials: LC
authors.lastname: Adès
authors.forename: Michel
authors.initials: M
authors.lastname: Tchan
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Louise C
authors.initials: LC
authors.lastname: Wilson
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Dian
authors.initials: D
authors.lastname: Donnai
authors.forename: Sahar
authors.initials: S
authors.lastname: Mansour
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Robertson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D001848:Bone Diseases, Developmental / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008875:Middle Aged; D010641:Phenotype; D017354:Point Mutation; D011230:Precancerous Conditions / Q000235:genetics*; D017434:Protein Structure, Tertiary; D012598:Sclerosis; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics*; D009396:Wilms Tumor / Q000235:genetics; D049951:X Chromosome Inactivation / Q000235:genetics
chemical_list: C517118:AMER1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D025521:Tumor Suppressor Proteins; C000600446:WTX protein, mouse