Pathogenic Mechanisms of Craniometaphyseal Dysplasia

Project Summary/Abstract
Investigating pathogenic mechanisms for rare Mendelian disorders is important not only to identify therapeutic
strategies for lifelong debilitating diseases but also to understand fundamental biological mechanisms. In this
renewal application, we propose mechanistic and translational studies for craniometaphyseal dysplasia (CMD),
an understudied craniotubular bone disorder characterized by lifelong progressing hyperostosis of craniofacial
bones and abnormal shape of long bones. Continued bone accrual in CMD can lead to excruciating
headaches, blindness, deafness, and facial palsy. Severe cases can be life-threatening. CMD patients are
treated with repetitive, costly and risky surgeries when corrections of facial deformity are needed or severe
neurological symptoms occur. Mutations in the progressive ankylosis protein (ANKH) and connexin 43 (Cx43)
have been identified as causes for autosomal dominant and recessive CMD, respectively. To study CMD, we
have generated state-of-the-art research tools, which include mouse models carrying CMD mutations, isogenic
human induced pluripotent stem cells (hiPSCs) with or without CMD mutations, and bone resorbing cells
(osteoclasts) derived from these hiPSCs. In the past funding period, we have discovered the rapid degradation
of mutant ANKH(Human)/ANK(Mouse) protein and studied negative effects of mutant ANKH/ANK on the
cytoskeleton, which determinates cell shape, size, and polarity. We also identified differentially expressed
proteins in CMD osteoclasts and preferential binding partners for mutant ANK protein. However, CMD
pathogenesis is not fully understood and potential therapeutics have not been explored.
Our long-term goal is to utilize our research findings for identifying potential therapeutic targets to reduce or
prevent the lifelong bone deposition in craniofacial bones. In the next 5 years, we will use animal models and
molecular and cellular methodologies that we have developed to focus on mechanistic investigations and
prepare for future clinical studies. Based on our preliminary data and previous publications we propose three
specific aims. We will study the impact of CMD-mutant ANK on cellular acidification of osteoclasts (Aim 1) and
on the bi-directional regulation between the cytoskeleton and an energy metabolism regulator in CMD (Aim 2).
These are likely novel dominant functions of mutant ANK leading to CMD. In Aim 3 we will identify biomarkers
that can be used to monitor the disease progression in patients and mouse models. We will also evaluate shifts
in biomarker expression in response to experimental treatment regimen in our model systems. We expect that
the proposed studies will give deeper insight into pathogenic mechanisms of CMD, knowledge needed to
discover candidate targets for therapeutics. Biomarkers that correspond to disease progression or treatment
efficacy will be the basis for future clinical studies.

Grant Number: 5R01DE025664-09
NIH Institute/Center: NIH
Principal Investigator: I-Ping Chen