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The Molecular Basis of Coordinated Overgrowth in Macrodactyly
Jennifer S. Lanni, PhD1, David S. Peal, PhD2, Felecia E. Cerrato, MPH2, Laura C. Nuzzi, BA2, Amir Taghinia, MD, MPH2, Matthew P. Harris, PhD2, Brian I. Labow, MD2.
1Wheaton College, Norton, MA, USA, 2Boston Children's Hospital, Boston, MA, USA.

BACKGROUND
Macrodactyly, a primary limb overgrowth disorder, remains a poorly understood congenital anomaly. Variable presentation overlapping with other overgrowth conditions, poor nomenclature, and the absence of animal models have hampered insights into this condition. Recently, somatic gain-of-function mutations in the kinase PIK3CA have been implicated in the pathogenesis of macrodactyly, various vascular anomalies, growth disorders, and malignancies. Mechanisms for PIK3CA-mediated overgrowth and the causes of phenotypic variability are lacking. In this study, we broadened genetic analysis of macrodactyly samples, identifying novel variants within human macrodactyly nerve and adipose tissue, permitting the development of a novel transgenic zebrafish model for macrodactyly.
METHODS
Explanted nerve, fat, and blood samples from affected human tissues were obtained during surgical debulking from macrodactyly patients and polydactyly controls. Targeted capture techniques identified mutations associated with human growth regulation (e.g. PIK3CA) as well as genes known to regulate coordinated growth in experimental models. Candidate genes were also identified in zebrafish using mutagenesis screening leading to fin overgrowth. Specific identified variants were reintroduced into the zebrafish to test sufficiency to recapitulate overgrowth seen in macrodactyly.
RESULTS
Somatic mutations in PIK3CA were observed in 18/18 macrodactyly patients, with mutational frequency greatest in nerve. Mutations were not found in control polydactyly tissue or the blood of macrodactyly patients. Mutagenesis screening of zebrafish with long fins demonstrated mutations leading to altered potassium channel function. Interestingly, analogous gain-of-function variants in the same potassium channel gene were identified in 6/18 macrodactyly patients, and in 5/6 patients with a clear median nerve territory distribution. We tested sufficiency of activated PIK3CA protein to cause fin overgrowth during zebrafish development. In 240 transgenic zebrafish containing the mutated human variant of PIK3CA, none manifested fin elongation. However, when the activated PIK3CA gene was introduced into zebrafish containing germline activated potassium channel mutations, 20/140 fish demonstrated focal, fin overgrowth.
CONCLUSIONS
Somatic mutations in PIK3CA occur in many disease states manifesting limb overgrowth, including macrodactyly. Unlike many PIK3CA overgrowth conditions, limb and digit overgrowth in macrodactyly maintains proportion, is devoid of vascular anomalies, and frequently follows a specific sensory nerve territory. Variants in potassium channel genes can lead to fin overgrowth in zebrafish and are found in human macrodactyly tissue. Transgenic zebrafish models suggest that in isolation, PIK3CA is insufficient to generate focal fin ray overgrowth. However, our model suggests a permissive role for potassium channel variants in PIK3CA-mediated overgrowth.


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