Copyright © 2008 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 82, Issue 2, 304-319, 31 January 2008
doi:10.1016/j.ajhg.2007.09.023
Article
Mutations in BMP4 Cause Eye, Brain, and Digit Developmental Anomalies: Overlap between the BMP4 and Hedgehog Signaling Pathways
Preeti Bakrania1, Maria Efthymiou2, Johannes C. Klein3, Alison Salt4, 5, David J. Bunyan6, 7, Alex Wyatt1, Chris P. Ponting1, 8, Angela Martin1, Steven Williams9, Victoria Lindley10, Joanne Gilmore11, Marie Restori4, Anthony G. Robson4, Magella M. Neveu4, Graham E. Holder4, J Richard O. Collin4, David O. Robinson6, 7, Peter Farndon10, Heidi Johansen-Berg3, Dianne Gerrelli2 and Nicola K. Ragge1, 4, 12, 
, 
1 Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK
2 Neural Development, Institute of Child Health, UCL, London WC1N 1EH, UK
3 Oxford Centre for Magnetic Resonance Imaging of the Brain, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
4 Moorfields Eye Hospital, London EC1V 2PD, UK
5 Wolfson Centre, Great Ormond Street Hospital, London WC1N 2AP, UK
6 Wessex Regional Genetics Laboratory, Salisbury District Hospital, Salisbury, Wiltshire SP2 8BJ, UK
7 Human Genetics Division, Southampton University School of Medicine, Southampton SO16 6YD, UK
8 MRC Functional Genetics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3QX, UK
9 Sheffield Regional Cytogenetics Service, Sheffield Children's NHS Foundation Trust, Sheffield S10 2TH, UK
10 West Midlands Regional Genetic Services, Birmingham Women's Hospital, Birmingham B15 2TG, UK
11 N East Thames Regional Cytogenetics service, Queens Square House, Institute of Neurology, Queens Square, London WC11 3BG, UK
12 Department of Ophthalmology, Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK
Corresponding authorAbstract
Developmental ocular malformations, including anophthalmia-microphthalmia (AM), are heterogeneous disorders with frequent sporadic or non-Mendelian inheritance. Recurrent interstitial deletions of 14q22-q23 have been associated with AM, sometimes with poly/syndactyly and hypopituitarism. We identify two further cases of AM (one with associated pituitary anomalies) with a 14q22-q23 deletion. Using a positional candidate gene approach, we analyzed the BMP4 (Bone Morphogenetic Protein-4) gene and identified a frameshift mutation (c.226del2, p.S76fs104X) that segregated with AM, retinal dystrophy, myopia, brain anomalies, and polydactyly in a family and a nonconservative missense mutation (c.278A→G, p.E93G) in a highly conserved base in another family. MR imaging and tractography in the c.226del2 proband revealed a primary brain developmental disorder affecting thalamostriatal and callosal pathways, also present in the affected grandmother. Using in situ hybridization in human embryos, we demonstrate expression of BMP4 in optic vesicle, developing retina and lens, pituitary region, and digits strongly supporting BMP4 as a causative gene for AM, pituitary, and poly/syndactyly. Because BMP4 interacts with HH signaling genes in animals, we evaluated gene expression in human embryos and demonstrate cotemporal and cospatial expression of BMP4 and HH signaling genes. We also identified four cases, some of whom had retinal dystrophy, with “low-penetrant” mutations in both BMP4 and HH signaling genes: SHH (Sonic Hedgehog) or PTCH1 (Patched). We propose that BMP4 is a major gene for AM and/or retinal dystrophy and brain anomalies and may be a candidate gene for myopia and poly/syndactyly. Our finding of low-penetrant variants in BMP4 and HH signaling partners is suggestive of an interaction between the two pathways in humans.
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