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

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Mutations in WNT7A Cause a Range of Limb Malformations, Including Fuhrmann Syndrome and Al-Awadi/Raas-Rothschild/Schinzel Phocomelia Syndrome C.G. Woods, S. Stricker, P. Seemann, R. Stern, J. Cox, E. Sherridan, E. Roberts, K. Springell, S. Scott, G. Karbani, S.M. Sharif, C. Toomes, J. Bond, D. Kumar, L. Al-Gazali, S. Mundlos The American Journal of Human Genetics Volume 79, Issue 2, Pages 402-408 (August 2006) DOI: 10.1086/506332 Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of families with Fuhrmann and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. A, Family 1, in which affected individuals received the diagnosis of “absence of ulnar and fibula with severe limb deficiency” (Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome). B, Family 2, in which affected individuals received the diagnosis of “fibular aplasia or hypoplasia, femoral bowing, and poly-, syn-, and oligodactyly (Fuhrmann syndrome).” The American Journal of Human Genetics 2006 79, 402-408DOI: (10.1086/506332) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 2 Clinical and radiographic features of an affected child from family 1. A, Overview of an affected female child, showing gross lower- and severe upper-limb anomalies. B, The child's right arm, showing absent ulnar bone, three missing fingers on the ulnar side, and no carpals. C, X-ray of the child's left limb, showing a single arm bone, absent carpal bones, and a thumb-like terminal appendage. D, X-ray of the child's pelvis and lower-limb remnants. Note severe hip dysplasia and femur hypoplasia. The American Journal of Human Genetics 2006 79, 402-408DOI: (10.1086/506332) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 3 Results of molecular genetic studies that determined that mutations in WNT7A cause Fuhrmann syndrome and Al-Awadi/Raas-Rothschild/Schinzel phocomelia syndrome. A, Chromosome 3, with the region of linkage to 3p25.1 expanded to show the markers homozygous in all affected family members (right of the bar) and heterozygous SNPs defining the extent of the linked region (left of the bar). The position of WNT7A is shown relative to the markers. B, WNT7A exon structure, with the start and stop codons identified. The two homozygous mutations found in the present study are shown. C, Protein sequence surrounding the WNT7A mutations found in this study, aligned with Wnt7a sequence from other species. The alanine altered in A109T and the arginine altered in R292C are invariant and are shaded gray. The sequence of the Drosophila melanogaster DWnt2, the orthologue of mammalian Wnt7a, is shown: the two equivalent amino acids are also conserved. The American Journal of Human Genetics 2006 79, 402-408DOI: (10.1086/506332) Copyright © 2006 The American Society of Human Genetics Terms and Conditions

Figure 4 Overexpression of wild-type WNT7A and WNT7A mutants in micromass cultures and chicken hindlimbs. A, Photographs from micromass cultures infected with indicated constructs, after 6 d in culture (stained with Alcian blue) and after 7 d in culture (stained for ALP activity). Wild-type WNT7A overexpression causes a strong inhibition of chondrogenesis, as indicated by the loss of Alcian blue staining (dark blue–stained cell aggregates); the repression of ALP activity (dark brown–stained cell aggregates); and the tendency to detach from the culture dish. Overexpression of WNT7A mutants resulted in a reduced inhibition of chondrogenesis compared with wild-type WNT7A. Detachment from the culture dish was significantly delayed. B, Quantification of nodule formation by measurement of Alcian blue–stained surface area. Overexpression of wild-type WNT7A and A109T-WNT7A suppress the formation of nodules, whereas cells infected with R292C-WNT7A are able to generate nodules, albeit at a significantly reduced level. C, Quantification of ALP by measurement of stained surface area. Both mutants, A109T-WNT7A and R292C-WNT7A, show significantly more ALP activity than wild-type WNT7A but less than uninfected control cultures. D, Alcian blue–stained skeletal preparations of chicken hindlimbs. The upper panel shows uninfected left hindlimb (control), and the lower panel demonstrates the effects of an overexpression of the indicated constructs in the right hindlimb. Wild-type WNT7A overexpression resulted in severe interference with limb patterning and cartilage formation. Phenotypes varied from almost-complete lack of limb cartilage elements to hypoplasia/aplasia of single elements, mostly in the zeugopod. Overexpression of A109T-WNT7A generally resulted in a milder phenotype. Hypoplasia of carpals was observed in most cases; in some specimens, the tibia was absent. Overexpression of R292C-WNT7A had no effect on limb development, which shows that this mutation ablated WNT7A activity in this experimental setting. The American Journal of Human Genetics 2006 79, 402-408DOI: (10.1086/506332) Copyright © 2006 The American Society of Human Genetics Terms and Conditions