Mutations in WNT7A cause a range of limb malformations, including Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome.
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.
Woods
C G
CG
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge CB2 2XY, UK. cw347@cam.ac.uk
Stricker
S
S
Seemann
P
P
Stern
R
R
Cox
J
J
Sherridan
E
E
Roberts
E
E
Springell
K
K
Scott
S
S
Karbani
G
G
Sharif
S M
SM
Toomes
C
C
Bond
J
J
Kumar
D
D
Al-Gazali
L
L
Mundlos
S
S
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*
D030161:Avian Proteins; D011518:Proto-Oncogene Proteins; C490509:WNT7A protein, Gallus gallus; C092778:WNT7A protein, human; D051153:Wnt Proteins