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Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways

Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways
Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways
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.
embryo, chromosome aberrations, nervous system malformations, physiology, dna primers, hypopituitarism, metabolism, human, retina, proteins, electrophysiology, cohort studies, pair 14, polydactyly, genetics, frameshift mutation, embryology, bone, protein, mutation, expression, animals, genes, humans, dna, research support, eye, research, hedgehog proteins, in situ hybridization, bone morphogenetic proteins, gene expression, signal transduction, chromosomes, family, brain
0002-9297
304-319
Bakrania, P.
705c184c-5420-42b1-8311-c9a2ffbc3206
Efthymiou, M.
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Klein, J.C.
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Salt, A.
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Bunyan, D.J.
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Wyatt, A.
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Ponting, C.P.
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Martin, A.
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Williams, S.
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Lindley, V.
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Gilmore, J.
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Restori, M.
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Robson, A.G.
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Neveu, M.M.
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Holder, G.E.
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Collin, J.R.
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Robinson, D.O.
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Farndon, P.
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Johansen-Berg, H.
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Gerrelli, D.
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Ragge, N.K.
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Bakrania, P.
705c184c-5420-42b1-8311-c9a2ffbc3206
Efthymiou, M.
c24db054-b98c-43cb-a2a1-3b3a89fc6f3c
Klein, J.C.
5e60d88c-cf55-4993-8830-61a66c024710
Salt, A.
bdb62f4f-2360-4ab1-93a8-975e300ee61c
Bunyan, D.J.
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Wyatt, A.
d5af8f30-69af-4e54-8e7d-e8a086e1860f
Ponting, C.P.
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Martin, A.
169f0afa-12fc-43b5-a72d-7bfc493aa170
Williams, S.
762dd529-2acb-40b8-acf3-e3488eec8506
Lindley, V.
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Gilmore, J.
4660c77a-fe9e-4b21-b393-f6354c57ba33
Restori, M.
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Robson, A.G.
d47651fd-5642-48e3-bb56-3b453edc7041
Neveu, M.M.
e5a47b01-32e6-4f2d-b4b2-729198ac07b5
Holder, G.E.
8bbec449-4f5a-4c8a-8732-09d2ae8c8847
Collin, J.R.
1a9f7acb-513f-43a3-a57a-4f6e0afacbb6
Robinson, D.O.
6b7e8cdc-b9c4-4ecf-a344-1bf0ae990f8a
Farndon, P.
542f912b-b301-4979-8124-79738f23a708
Johansen-Berg, H.
d915c19a-9631-42f5-91a1-e8ac7bca9263
Gerrelli, D.
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Ragge, N.K.
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Bakrania, P., Efthymiou, M., Klein, J.C., Salt, A., Bunyan, D.J., Wyatt, A., Ponting, C.P., Martin, A., Williams, S., Lindley, V., Gilmore, J., Restori, M., Robson, A.G., Neveu, M.M., Holder, G.E., Collin, J.R., Robinson, D.O., Farndon, P., Johansen-Berg, H., Gerrelli, D. and Ragge, N.K. (2008) Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways. The American Journal of Human Genetics, 82 (2), 304-319. (doi:10.1016/j.ajhg.2007.09.023).

Record type: Article

Abstract

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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More information

Published date: January 2008
Keywords: embryo, chromosome aberrations, nervous system malformations, physiology, dna primers, hypopituitarism, metabolism, human, retina, proteins, electrophysiology, cohort studies, pair 14, polydactyly, genetics, frameshift mutation, embryology, bone, protein, mutation, expression, animals, genes, humans, dna, research support, eye, research, hedgehog proteins, in situ hybridization, bone morphogenetic proteins, gene expression, signal transduction, chromosomes, family, brain

Identifiers

Local EPrints ID: 59458
URI: https://eprints.soton.ac.uk/id/eprint/59458
ISSN: 0002-9297
PURE UUID: 4eb776a3-a02b-4808-8ee6-be5137b9df65

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Date deposited: 03 Sep 2008
Last modified: 13 Mar 2019 20:30

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Contributors

Author: P. Bakrania
Author: M. Efthymiou
Author: J.C. Klein
Author: A. Salt
Author: D.J. Bunyan
Author: A. Wyatt
Author: C.P. Ponting
Author: A. Martin
Author: S. Williams
Author: V. Lindley
Author: J. Gilmore
Author: M. Restori
Author: A.G. Robson
Author: M.M. Neveu
Author: G.E. Holder
Author: J.R. Collin
Author: D.O. Robinson
Author: P. Farndon
Author: H. Johansen-Berg
Author: D. Gerrelli
Author: N.K. Ragge

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