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3-M syndrome: a growth disorder associated with IGF2 silencing

3-M syndrome: a growth disorder associated with IGF2 silencing
3-M syndrome: a growth disorder associated with IGF2 silencing
3-M syndrome is an autosomal recessive disorder characterised by pre- and postnatal growth restriction, facial dysmorphism, normal intelligence and radiological features (slender long bones and tall vertebral bodies). It is known to be caused by mutations in the genes encoding Cullin 7, Obscurin like-1 and Coiled-Coil Domain Containing 8. The mechanisms through which mutations in these genes impair growth are unclear. The aim of this study was to identify novel pathways involved in the growth impairment in 3-M syndrome. RNA was extracted from fibroblast cell lines derived from four 3-M syndrome patients and 3 control subjects, hybridised to Affymetrix HU 133 plus 2.0 arrays with quantitative real time PCR used to confirm changes found on microarray. IGF-II protein levels in serum and conditioned cell culture medium were measured by ELISA. Of the top 10 downregulated probesets 3 represented IGF2 while H19 was identified as the 23rd most upregulated probeset. QRT-PCR confirmed upregulation of H19(p<0.001) and downregulation of IGF2 (p<0.001). Levels of IGF-II secreted into conditioned cell culture medium were higher for control fibroblasts than for 3-M fibroblasts (10.2 ± 2.9ng/ml v 0.6 ± 0.9ng/ml, p<0.01). 3-M syndrome is associated with a gene expression profile of reduced IGF2 expression and increased H19 expression similar to that found in Silver Russell syndrome. Loss of autocrine IGF-II in the growth plate may be associated with the short stature seen in children with 3-M syndrome.
225-235
Murray, P.G.
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Hanson, D.
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Coulson, T.
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Stevens, A.
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Whatmore, A.J.
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Poole, R.L.
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Mackay, D.J.
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Black, G.C.
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Clayton, P.E.
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Murray, P.G.
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Hanson, D.
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Coulson, T.
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Stevens, A.
ee290275-c6b9-473b-a798-8cc38ee51cb5
Whatmore, A.J.
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Poole, R.L.
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Mackay, D.J.
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Black, G.C.
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Clayton, P.E.
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Murray, P.G., Hanson, D., Coulson, T., Stevens, A., Whatmore, A.J., Poole, R.L., Mackay, D.J., Black, G.C. and Clayton, P.E. (2013) 3-M syndrome: a growth disorder associated with IGF2 silencing. Endocrine Connections, 2 (4), 225-235. (doi:10.1530/EC-13-0065). (PMID:24148222)

Record type: Article

Abstract

3-M syndrome is an autosomal recessive disorder characterised by pre- and postnatal growth restriction, facial dysmorphism, normal intelligence and radiological features (slender long bones and tall vertebral bodies). It is known to be caused by mutations in the genes encoding Cullin 7, Obscurin like-1 and Coiled-Coil Domain Containing 8. The mechanisms through which mutations in these genes impair growth are unclear. The aim of this study was to identify novel pathways involved in the growth impairment in 3-M syndrome. RNA was extracted from fibroblast cell lines derived from four 3-M syndrome patients and 3 control subjects, hybridised to Affymetrix HU 133 plus 2.0 arrays with quantitative real time PCR used to confirm changes found on microarray. IGF-II protein levels in serum and conditioned cell culture medium were measured by ELISA. Of the top 10 downregulated probesets 3 represented IGF2 while H19 was identified as the 23rd most upregulated probeset. QRT-PCR confirmed upregulation of H19(p<0.001) and downregulation of IGF2 (p<0.001). Levels of IGF-II secreted into conditioned cell culture medium were higher for control fibroblasts than for 3-M fibroblasts (10.2 ± 2.9ng/ml v 0.6 ± 0.9ng/ml, p<0.01). 3-M syndrome is associated with a gene expression profile of reduced IGF2 expression and increased H19 expression similar to that found in Silver Russell syndrome. Loss of autocrine IGF-II in the growth plate may be associated with the short stature seen in children with 3-M syndrome.

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e-pub ahead of print date: 22 October 2013
Published date: November 2013
Organisations: Human Development & Health

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Local EPrints ID: 359258
URI: http://eprints.soton.ac.uk/id/eprint/359258
PURE UUID: 6e1ad298-8705-4707-a9bd-072be2d280f6
ORCID for D.J. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

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Date deposited: 24 Oct 2013 12:56
Last modified: 28 Oct 2023 01:44

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Contributors

Author: P.G. Murray
Author: D. Hanson
Author: T. Coulson
Author: A. Stevens
Author: A.J. Whatmore
Author: R.L. Poole
Author: D.J. Mackay ORCID iD
Author: G.C. Black
Author: P.E. Clayton

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