Germline mutations in WTX cause a sclerosing skeletal dysplasia but do not predispose to tumorigenesis.
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.
Jenkins
Zandra A
ZA
Departments of Paediatrics, Dunedin School of Medicine, Otago University, Dunedin 9054, New Zealand.
van Kogelenberg
Margriet
M
Morgan
Tim
T
Jeffs
Aaron
A
Fukuzawa
Ryuji
R
Pearl
Esther
E
Thaller
Christina
C
Hing
Anne V
AV
Porteous
Mary E
ME
Garcia-Miñaur
Sixto
S
Bohring
Axel
A
Lacombe
Didier
D
Stewart
Fiona
F
Fiskerstrand
Torunn
T
Bindoff
Laurence
L
Berland
Siren
S
Adès
Lesley C
LC
Tchan
Michel
M
David
Albert
A
Wilson
Louise C
LC
Hennekam
Raoul C M
RC
Donnai
Dian
D
Mansour
Sahar
S
Cormier-Daire
Valérie
V
Robertson
Stephen P
SP
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
C517118:AMER1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D025521:Tumor Suppressor Proteins; C000600446:WTX protein, mouse