Expression Analysis of Macrodactyly Identifies Pleiotrophin Upregulation

Lau, Frank H.; Xia, Fang; Kaplan, Adam; Cerrato, Felecia; Greene, Arin K.; Taghinia, Amir H.; Cowan, Chad A.; Labow, Brian I.

doi:10.1371/journal.pone.0040423

Cited by 9 publications

(5 citation statements)

References 27 publications

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“…Corresponding to these patterns of PIK3CA localization, we also found co-expression of active p-AKT and p-mTOR in these tissues as well, though not as prevalent as in nerve tissue ( Figure 2C ). In contrast, Pleiotrophin (PTN), a gene we found highly differentially expressed in macrodactyly (Lau et al, 2012), was predominantly expressed in smooth muscle of the vascular tissue. The observed patterns of expression in macrodactyly tissue were generally consistent with that seen in polydactyly samples which serve as a ‘nonaffected’, or wildtype PIK3CA, control tissue ( Supplementary Figure 1 ).…”

Section: Resultsmentioning

confidence: 82%

Characterization of coordinated growth in macrodactyly caused by somatic mosaic activating mutations inPIK3CA

McNamara

Lanni

Daane

et al. 2022

Preprint

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Localized somatic overgrowth disorders that occur during development can be debilitating, and most often require surgical intervention. Although underlying genetic changes associated with overgrowth have been identified in the majority of cases, the cause of the dysregulated growth and its presentation is unknown. Here we detail current work on a specific overgrowth disorder, macrodactyly, in which overgrowth is localized and shows integration with developmental patterning of the limb, providing coordination of the resulting overgrowth structure. We provide clinical analysis of presentation of macrodactyly in a cohort of patients and provide experimental evidence for nerve and vascular-biased regulation of growth. We provide the first animal model that recapitulates macrodactyly and provide evidence that genetic modifiers may underlie the development of this disorder. The unique presentation of macrodactyly provides a framework to identify the causes and regulatory activities that shape hyperplastic signals that lead to integrated patterning in overgrowth. Use of our experimental model suggests potential for genetic modifiers as important for the particular presentation of this disorder over other PIK3CA-related growth disorders.

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Section: Resultsmentioning

confidence: 82%

Characterization of coordinated growth in macrodactyly caused by somatic mosaic activating mutations inPIK3CA

McNamara

Lanni

Daane

et al. 2022

Preprint

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“…Macrodactyly is an uncommon congenital nervous system disease, and is characterized by the proliferation of nerve fibers, vessels, subcutaneous fat and other tissues (1)(2)(3). The pathogenesis of macrodactyly remains to be fully elucidated, therefore, the identification of genes expressed at high levels in macrodactyly may reveal factors, which promote nerve overgrowth and contribute to the pathogenesis of this condition.…”

Section: Discussionmentioning

confidence: 99%

“…The malformation often occurs unilaterally or asymmetrically and affects more than one digit or toe. The clinical conditions associated with this deformity are carpal tunnel syndrome, syndactylism, neurofibromatosis type 1 cafe au lait spots, lipoma and nevi (1)(2)(3).…”

Section: Introductionmentioning

confidence: 99%

GRIN3A and MAPT stimulate nerve overgrowth in macrodactyly

Shi

Jin

et al. 2016

Molecular Medicine Reports

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As an uncommon and congenital condition, macrodactyly is characterized by an increase in the size of all the elements or structures of the digits or toes; however, the underlying pathogenesis remains to be fully elucidated. In the present study, the gene expression profiles of abnormal nerves were examined in three patients with macrodactyly using microarray analysis to identify potential genes contributing to nerve overgrowth. Gene expression profiling in the nerve tissue samples were scanned using the microarray and the differentially expressed genes were verified at the transcription level using reverse transcription‑quantitative polymerase chain reaction analysis. Western blot analysis was used to determine the expression of target genes at the translational level. To confirm the upregulated genes during the process of nerve proliferation, SH‑SY5Y cells were induced to differentiate into a neuronal‑like phenotype using retinoic acid. A total of 165 genes showed significant changes (≥5‑fold) in gene expression, which may be associated with the development of limbs in macrodactyly. Glutamate ionotropic receptor NMDA 3A (GRIN3A) and microtubule‑associated protein tau (MAPT) were identified as important contributors in promoting nerve overgrowth. Furthermore, it was identified that GRIN3A and MAPT were regulated by the cAMP‑protein kinase A and extracellular signal‑regulated kinase 1/2 pathways, respectively. The identification of genes expressed at high levels in macrodactyly may reveal potential factors, which contribute to abnormal nerve proliferation and underpin the pathogenesis of macrodactyly, and provide potential application targets in nerve tissue regeneration engineering.

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“…We utilized the microarray gene sets of GSE35820 (macrodactyly), GSE15773 (fat group 1), GSE13506 (fat group 2) and GSE14905 (skin group). In macrodactyly expression data (GSE35820), total RNA of 4 pediatric patients, including a 15-month-old boy and an 8-year-old girl who underwent elective surgical debulking at Massachusetts General Hospital or at Children's Hospital Boston between June 2009 and April 2011, were extracted [10]. In the fat group (GSE15773 [17] and GSE13506 [18]), adipose tissue samples were taken from subcutaneous fat of lower abdominal wall.…”

Section: Expression Microarray Data From Gene Expression Omnibus (Geo)mentioning

confidence: 99%

“…Lau et al described pleiotrophin (PTN), a developmental cytokine, was significantly overexpressed across all their macrodactyly samples [10]. However, previous research has provided the limited pathological insights to describe the molecular mechanism in a better way.…”

Section: Introductionmentioning

confidence: 99%

Signature Genes in Macrodactyly through Transcriptome Network Analysis Reveal their Association of Lipid Metabolism

Choi

Lee

2017

Korean J Phys Anthropol

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: Macrodactyly is one of the most difficult hand anomalies to treat not only surgically but medically as well. Little is known about the molecular pathways and lipid metabolism of this disease. To elucidate the potential mechanism of macrodactyly progress, we used the bioinformatical analysis including quantile normalization, principal component analysis, heatmap and volcano plot. For the functional bioinformatical study, lipid, lipoprotein and phospholipid metabolism of Kyoto Encyclopedia of Genes and Genomes, Wiki Pathways, and Reactome Pathway were utilized to compare the differentially expressed genes in macrodactyly with control group. We found up-regulation of CDK6 and E2F1, which are associated with the mitotic cell cycle of cancer cells. PIK3CG, associated with cancer and lipid metabolism, was also enriched in macrodactyly. In down-regulated genes, PTEN was highlighted in lipid metabolism, phosphatidylinositol signaling system and insulin signaling. ABCD3, related in peroxisomal import of fatty acids, was also down-regulated. In this study, we predicted the pathogenic candidate genes as well as the potential molecular pathways related to macrodactyly by identifying the signature genes. Signature genes through systems bioinformatical analysis can be utilized to catch the insight of the molecular pathogenesis of macrodactyly.

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Expression Analysis of Macrodactyly Identifies Pleiotrophin Upregulation

Cited by 9 publications

References 27 publications

Characterization of coordinated growth in macrodactyly caused by somatic mosaic activating mutations inPIK3CA

Characterization of coordinated growth in macrodactyly caused by somatic mosaic activating mutations inPIK3CA

GRIN3A and MAPT stimulate nerve overgrowth in macrodactyly

Signature Genes in Macrodactyly through Transcriptome Network Analysis Reveal their Association of Lipid Metabolism

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