Abstract
3-M syndrome is an autosomal recessive disorder characterised by pre- and post-natal 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 three 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 conditioned cell culture media were measured by ELISA. Of the top 10 downregulated probesets, three 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 those for 3-M fibroblasts (10.2±2.9 vs 0.6±0.9 ng/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.
Highlights
3-M syndrome is an autosomal recessive disorder characterised by impaired pre- and post-natal growth, facial dysmorphism, prominent heels, normal intelligence and, in some, radiological features
It is caused by loss offunction mutations in the genes encoding cullin 7 (CUL7) [1], obscurin-like 1 (OBSL1) [2] and coiled-coil domain containing 8 (CCDC8) [3]
Altered IGF-I signalling with increased activation of the downstream signalling molecule AKT was identified in Cul7K/K mouse embryonic fibroblasts (MEFs) [9], associated with poor cell growth and senescence
Summary
3-M syndrome (named after the first three authors to describe the condition) is an autosomal recessive disorder characterised by impaired pre- and post-natal growth, facial dysmorphism (triangular shaped face, anteverted nares, full fleshy lips), prominent heels, normal intelligence and, in some, radiological features (slender long bones and tall vertebral bodies) It is caused by loss offunction mutations in the genes encoding cullin 7 (CUL7) [1], obscurin-like 1 (OBSL1) [2] and coiled-coil domain containing 8 (CCDC8) [3]. 3-M syndrome is considered to be a relatively uncommon disorder, it is probably an under recognised condition [6]; its core characteristics of pre- and post-natal growth impairment are shared with all small for gestational age (SGA) children with failure of catch up growth This includes many children in whom there is as yet no clear mechanism of growth impairment. An understanding of the mechanisms of growth impairment in 3-M syndrome could lead to insights into the causation of poor growth in other SGA children and potential targets for molecular diagnostics
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