# Pathogenic Mechanisms of Craniometaphyseal Dysplasia

> **NIH NIH R01** · UNIVERSITY OF CONNECTICUT SCH OF MED/DNT · 2020 · $398,750

## Abstract

Project Summary/Abstract
Developing therapies for rare genetic diseases is as important as for more common disorders because many
of these patients are suffering from lifelong debilitating and life-threatening symptoms with treatment being
limited or non-existent. The key for developing therapeutic interventions is to understand the cellular and
molecular consequences of genomic abnormalities identified in these diseases. This proposal aims to identify
pathogenic mechanisms of craniometaphyseal dysplasia (CMD), characterized by thickened craniofacial bones
and widened metaphyses of long bones. The onset of CMD begins early in infancy and cranifacial bones
progressively thicken throughout life, which can result in life-threatening consequences for patients. The
obstruction of nerves by narrowing cranial foramina often leads to blindness, deafness, facial paralysis and
severe headache even in young children. To date, there is no treatment for CMD other than repetitive and risky
surgeries. We have generated a mouse model carrying a CMD mutation and human induced pluripotent stem
cells (hiPSCs) from CMD patients and healthy donors. Cell-autonomous defects in osteoblasts and osteoclasts
(OCs) in a mouse model for CMD have been reported. OCs are significantly smaller and functioanlly deficient
in CMD mice and CMD patients. We use OCs to study unique mutational effects because OCs show the most
notable differences between CMD mice and mice that have no ANK protein.
To gain insight into how mutations in the progressive ankylosis gene ANKH (human) and ANK (mouse
orthologue) cause CMD, three Specific Aims are proposed to test the central hypothesis that mutations in
ANKH cause CMD by reducing levels of functional ANKH and by decreasing Ca2+/CaM signaling, which results
in defective actomyosin complexes. Aim 1 will determine the mechanisms regulating expression and
localization of CMD mutant ANK/ANKH. Aim 2 will determine the role of CMD mutant ANK on calcium signaling
in osteoclasts. Aim 3 will identify the mechanisms leading to defective actomyosin complexes in CMD
osteoclasts. Findings from this project will be the basis for a future translational study to focus on developing
therapeutic interventions for CMD. This project is expected to have a high impact on investigations of similar
rare genetic bone disorders as well as on a better understanding of unrecognized roles of ANK/ANKH in
normal bone development and beyond.

## Key facts

- **NIH application ID:** 9962970
- **Project number:** 5R01DE025664-05
- **Recipient organization:** UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
- **Principal Investigator:** I-Ping Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $398,750
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9962970

## Citation

> US National Institutes of Health, RePORTER application 9962970, Pathogenic Mechanisms of Craniometaphyseal Dysplasia (5R01DE025664-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9962970. Licensed CC0.

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