# Genetics and Molecular Mechanisms Underlying Overgrowth Disorders of the Limb

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $367,275

## Abstract

Summary
The orchestration of growth and differentiation during development is essential for normal mechanical and
physiological function of organs and appendages. Despite its importance, the regulation of how coordinated
growth occurs such that proportion is maintained is not well understood. To gain insight into this process, we
studied the congenital overgrowth disorder macrodactyly characterized by local giganticism of the digits of the
hand and feet. Macrodactyly is a unique growth disorder in that the skeletal and soft tissue elements of the
digits including nerve, vasculature, muscle and bone are enlarged, however organized such that larger digits
form. Thus, patients with macrodactyly represent a unique biologic opportunity to explore fundamental
mechanisms of how growth, size and proportion are coordinated within and between tissues. We have
identified a specific somatic activating mutation in the catalytic subunit of phosphoinositide 3 kinase (PI3K),
encoded by the gene PIK3CA, within affected tissue of macrodactyly patients. This mutation is also commonly
found in cancer and other overgrowth disorders; thus, this mutation alone cannot explain the coordinated
growth response observed in macrodactyly. How does this particular mutation lead to overgrowth that is
coordinated and patterned during the development of the limbs? The restriction of overgrowth to the digits in
these patients as opposed to the proximal limb, suggests a role for tissue interactions in the distal limb during
development to regulate patterned growth and size. Additionally, we have identified potential modifier
mutations arising in concert with PIK3CA that may be essential for PI3K regulation of overgrowth. We
hypothesize that PI3K-mediated signaling coordinates growth through specific paracrine signaling from
sensory neural tissues during development in a manner that is dependent on signaling between the apical
ectodermal ridge (AER) and mesenchymal tissues during limb development. We propose to investigate the
regulation of coordinated growth by PI3K through: 1) identification and localization of the affected cells and
tissues containing mutant PIK3CA in macrodactyly patients and examination of the effect of these mutant cells
on adjacent tissues; 2) use of novel zebrafish models to dissect the genetic and developmental causes of
overgrowth though systematic analysis of newly identified secondary modifier mutations in regulating PIK3CA
function and 3) the use of a conditional knockin mouse model of activated PIK3CA to test the sufficiency of
increased PI3K signaling within specific tissues of the developing mouse limb to phenocopy macrodactyly. The
proposed research will define the molecular and tissue level regulation of organ size and growth that will lead
to new treatment modalities for a host of overgrowth and neoplastic conditions and yield new strategies for
enhancing tissue repair and organ regeneration.

## Key facts

- **NIH application ID:** 9915956
- **Project number:** 5R01HD084985-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Matthew P Harris
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $367,275
- **Award type:** 5
- **Project period:** 2016-07-07 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9915956

## Citation

> US National Institutes of Health, RePORTER application 9915956, Genetics and Molecular Mechanisms Underlying Overgrowth Disorders of the Limb (5R01HD084985-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9915956. Licensed CC0.

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