title: Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome.
abstract: Fuhrmann syndrome and the Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome are considered to be distinct limb-malformation disorders characterized by various degrees of limb aplasia/hypoplasia and joint dysplasia in humans. In families with these syndromes, we found homozygous missense mutations in the dorsoventral-patterning gene WNT7A and confirmed their functional significance in retroviral-mediated transfection of chicken mesenchyme cell cultures and developing limbs. The results suggest that a partial loss of WNT7A function causes Fuhrmann syndrome (and a phenotype similar to mouse Wnt7a knockout), whereas the more-severe limb truncation phenotypes observed in Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome result from null mutations (and cause a phenotype similar to mouse Shh knockout). These findings illustrate the specific and conserved importance of WNT7A in multiple aspects of vertebrate limb development.
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 2XY, UK. cw347@cam.ac.uk
authors.forename: C G
authors.initials: CG
authors.lastname: Woods
authors.forename: S
authors.initials: S
authors.lastname: Stricker
authors.forename: P
authors.initials: P
authors.lastname: Seemann
authors.forename: R
authors.initials: R
authors.lastname: Stern
authors.forename: J
authors.initials: J
authors.lastname: Cox
authors.forename: E
authors.initials: E
authors.lastname: Sherridan
authors.forename: E
authors.initials: E
authors.lastname: Roberts
authors.forename: K
authors.initials: K
authors.lastname: Springell
authors.forename: S
authors.initials: S
authors.lastname: Scott
authors.forename: G
authors.initials: G
authors.lastname: Karbani
authors.forename: S M
authors.initials: SM
authors.lastname: Sharif
authors.forename: C
authors.initials: C
authors.lastname: Toomes
authors.forename: J
authors.initials: J
authors.lastname: Bond
authors.forename: D
authors.initials: D
authors.lastname: Kumar
authors.forename: L
authors.initials: L
authors.lastname: Al-Gazali
authors.forename: S
authors.initials: S
authors.lastname: Mundlos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D030161:Avian Proteins / Q000235:genetics; D002645:Chickens; D020219:Chondrogenesis / Q000235:genetics / Q000502:physiology; D004480:Ectromelia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D017353:Gene Deletion; D008040:Genetic Linkage; D006801:Humans; D018878:Limb Buds / Q000254:growth & development / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009924:Organ Culture Techniques; D010375:Pedigree; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D011859:Radiography; D051153:Wnt Proteins / Q000235:genetics*
chemical_list: D030161:Avian Proteins; D011518:Proto-Oncogene Proteins; C490509:WNT7A protein, Gallus gallus; C092778:WNT7A protein, human; D051153:Wnt Proteins