# Mechanistic Ancillary Study to the Natural History Study of ADO2 to Determine Clinical Severity

> **NIH NIH R21** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $231,220

## Abstract

Abstract NIAMS Supplement
Abstract
Autosomal dominant osteopetrosis type 2 (ADO2) is a rare disorder resulting from impaired osteoclastic bone
resorption due to mutations in the Chloride Channel 7 gene, which cause disease by a dominant negative
mechanism. Penetrance is approximately 66% and disease severity varies widely, even within the same family.
Affected individuals typically have at least one significant clinical manifestation including fractures,
osteonecrosis, osteomyelitis, blindness, or bone marrow failure. We previously demonstrated that osteoclasts
cultured from monocytes of individuals with dominant osteopetrosis had markedly decreased pit resorption
compared to osteoclasts isolated from carriers who had the same CLCN7 mutation. The osteoclasts from
carriers actually resorbed bone similarly to those from control individuals. These studies demonstrated that
osteoclast function, rather than the bone microenvironment, was responsible for the differences in bone
between affected individuals and carriers. However, the mechanisms that determine influence disease
penetrance and severity are unknown. This study will use a well-characterized cohort of subjects from an
ongoing natural history study to study these mechanisms. Specifically, we will perform RNA-sequencing
analysis using RNA isolated from osteoclasts from affected individuals, asymptomatic carriers and controls
(without CLCN7 mutations) and determine differences in RNA expression to identify pathways/networks that
differ between affected individuals, carriers and controls. Successful completion of the proposed aims will
provide critical data revealing the pathways/networks determining whether an individual with a CLCN7
mutation clinically manifests with severe features or as a nonpenetrant carrier. In addition to providing
important information about basic osteoclast biology, understanding the pathways/networks controlling
penetrance and clinical severity will enable us to design targeted therapeutics for ADO2.

## Key facts

- **NIH application ID:** 10375070
- **Project number:** 1R21AR080424-01
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Michael J Econs
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $231,220
- **Award type:** 1
- **Project period:** 2021-09-24 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10375070

## Citation

> US National Institutes of Health, RePORTER application 10375070, Mechanistic Ancillary Study to the Natural History Study of ADO2 to Determine Clinical Severity (1R21AR080424-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10375070. Licensed CC0.

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