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Mutations in WNT7A Cause a Range of Limb Malformations, Including Fuhrmann Syndrome and Al-Awadi/Raas-Rothschild/Schinzel Phocomelia Syndrome

2006; Elsevier BV; Volume: 79; Issue: 2 Linguagem: Inglês

10.1086/506332

1537-6605

C. Geoffrey Woods, Sigmar Stricker, Petra Seemann, Rowena Stern, James J. Cox, E. Sherridan, Emma Roberts, Kelly Springell, Simon Scott, Gulshan Karbani, Saghira Malik Sharif, Carmel Toomes, Jacquelyn Bond, Dheeraj Kumar, Lihadh Al‐Gazali, Stefan Mundlos,

Tumors and Oncological Cases

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.