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Expression Analysis of Macrodactyly Identifies Pleiotrophin Upregulation
Frank Lau, MD1, Fang Xia2, Adam Kaplan2, Felecia Cerrato1, Arin K. Greene, MD1, Amir Taghinia, MD1, Chad A. Cowan, PhD2, Brian I. Labow, MD1.
1Children's Hospital Boston, Boston, MA, USA, 2Massachusetts General Hospital, Boston, MA, USA.

BACKGROUND:Macrodactyly is a rare family of congenital disorders characterized by the diffuse enlargement of 1 or more digits. Multiple tissue types within the affected digits are involved, but skeletal patterning and gross morphological features are preserved. Not all tissues are equally involved and there is marked heterogeneity with respect to clinical phenotype. The molecular mechanisms responsible for these growth disturbances offer unique insight into normal limb growth and development, in general. To date, no genes or loci have been implicated in the development of macrodactyly.
METHODS: In this study, we performed transcriptional profiling of macrodactyly tissue. RNA was isolated from 4 macrodactyly adipose tissue samples and hybridized to Affymetrix U133A Plus 2.0 microarrays. Microarray data were analyzed with principal component analysis, hierarchical clustering, and gene enrichment analysis. Significant results were confirmed using quantitative real time polymerase chain reaction and immunohistochemistry.
RESULTS: 7,295 genes are differentially expressed in macrodactyly adipose tissue compared to subcutaneous adipose tissue. In particular, pleiotrophin (PTN) was 127.6-fold (p-value = 0.049) overexpressed across all our macrodactyly samples. At the biological pathway level, gene enrichment analysis found that subcutaneous adipose tissue (SAT) was enriched for classic adipose tissue gene ontology categories such as “regulation of catabolic processes” and “response to insulin stimulus”. In contrast, macrodactyly tissues demonstrated enrichment of vastly different gene ontology categories such as “extracellular space” and “pattern binding”.
CONCLUSIONS:Pleiotrophin is a promising candidate gene for the pathogenesis of macrodactyly because it promotes growth of nearly all the tissues affected by macrodactyly, including nerve, skin, bone, and cartilage. PTN thus represents a promising target for further investigation into the etiology of overgrowth phenotypes.

Top 10 greatest fold-change probesets in macrodactyly
Probeset IDGeneDescriptionp-valueFold-Change (vs. subcutaneous adipose tissue)
223475_atCRISPLD1cysteine-rich secretory protein LCCL domain containing 11.85E-4221.42
203913_s_atHPGDhydroxyprostaglandin dehydrogenase 15-(NAD)1.40E-4515.71
216834_atRGS1regulator of G-protein signaling 12.72E-2514.19
205430_atBMP5bone morphogenetic protein 5013.97
209189_atFOSFBJ murine osteosarcoma viral oncogene homolog3.03E-1512.82

Top 10 greatest fold-change probesets in subcutaneous adipose tissue
Probeset IDGeneDescriptionp-valueFold-Change (vs. Macrodactyly)
214456_x_atSAA1 /// SAA2serum amyloid A1 /// serum amyloid A24.20E-4591.68
208607_s_atSAA1 /// SAA2serum amyloid A1 /// serum amyloid A24.84E-2672.59
204424_s_atLMO3LIM domain only 3 (rhombotin-like 2)017.56
214146_s_atPPBPpro-platelet basic protein (chemokine (C-X-C motif) ligand 7)1.72E-2116.27
228434_atBTNL9butyrophilin-like 9014.31
211699_x_atHBA1 /// HBA2hemoglobin, alpha 1 /// hemoglobin, alpha 2014.28
209458_x_atHBA1 /// HBA2hemoglobin, alpha 1 /// hemoglobin, alpha 2013.49
204018_x_atHBA1 /// HBA2hemoglobin, alpha 1 /// hemoglobin, alpha 2012.66
204105_s_atNRCAMneuronal cell adhesion molecule2.39E-2712.49

Enriched gene ontology categories in macrodactyly
# of genesP-adjustedGO IDGO Category
60.001GO:0071363cellular response to growth factor stimulus
60.039GO:0070848response to growth factor stimulus
100.048GO:0030199collagen fibril organization
180.011GO:0001501skeletal system development
190GO:0005578proteinaceous extracellular matrix
220GO:0031012extracellular matrix
300GO:0005539glycosaminoglycan binding
340GO:0001871pattern binding
340GO:0030247polysaccharide binding

Enriched gene ontology categories in subcutaneous adipose tissue
# of genesP-adjustedGO IDGO Category
30.002GO:0015671oxygen transport
120.013GO:0003995acyl-CoA dehydrogenase activity
170GO:0046320regulation of fatty acid oxidation
240.023GO:0032869cellular response to insulin stimulus
360.004GO:0032868response to insulin stimulus
550.013GO:0051056regulation of small GTPase mediated signal transduction
600.049GO:0006732coenzyme metabolic process
870.004GO:0009894regulation of catabolic process

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