# Molecular Etiology of Spondyloepimetaphyseal Dysplasia with Joint Laxity - Leptodactylic Type

> **NIH NIH F31** · UNIVERSITY OF VERMONT & ST AGRIC COLLEGE · 2021 · $34,070

## Abstract

PROJECT SUMMARY
 Skeletal dysplasias are disorders of skeletal development and occur at a rate of approximately 1 in 5000
births. DNA sequencing is capable of identifying causative genes for these disorders, but mechanistic studies
are needed to understand how identified mutations cause abnormal bone growth. This proposal addresses the
mechanistic gap in knowledge for spondyloepimetaphyseal dysplasia with joint laxity- leptodactylic type
(SEMDJL2), a skeletal dysplasia characterized by defects in endochondral bone formation. Causative dominant
mutations in the gene KIF22 have been identified in SEMDJL2 patients. However, the function of KIF22, a kinesin
motor protein, in bone development and the consequences of single amino acid changes in KIF22 on this process
are not known. Endochondral bone growth requires the differentiation of mesenchymal stem cells to
chondrocytes and osteoblasts. Chondrocytes proliferate and produce a calcified cartilage template for bone
growth. Upon chondrocyte hypertrophy, osteoblasts are recruited to the calcified cartilage and deposit bone
matrix. We hypothesize that mutations in KIF22 result in disruption of this process via defects in cell division and
proliferation, defects in the differentiation of progenitors to chondroctyes and osteoblasts, or defects in both
division and differentiation. To test the function of KIF22 in division and proliferation of progenitor cells at the
cellular level, we will use a combination of fixed and live cell imaging to assess the ability of KIF22 with SEMDJL2-
derived mutations to generate forces for the movement of chromosome arms in mitotic cells. Consequent cell
cycle arrest or reduction in proliferation will be assessed. To determine whether mutations in KIF22 result in
SEMDJL2 pathology due to defects in pluripotent mesenchymal stem cell differentiation, we will induce
differentiation of cells to chondrocytes and osteoblasts in vitro. Differentiation and maturation will be assessed
in these systems by histological staining for matrix production and mineralization, as well as expression levels
of markers indicative of chondrocytes, osteoblasts, or osteocytes. Together, these assays will allow us to
determine the mechanism by which mutations in KIF22 affect endochondral bone growth by combining expertise
in cell division with expertise in the control of bone development.

## Key facts

- **NIH application ID:** 10166771
- **Project number:** 5F31AR074887-03
- **Recipient organization:** UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
- **Principal Investigator:** Alex Thompson
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $34,070
- **Award type:** 5
- **Project period:** 2019-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166771

## Citation

> US National Institutes of Health, RePORTER application 10166771, Molecular Etiology of Spondyloepimetaphyseal Dysplasia with Joint Laxity - Leptodactylic Type (5F31AR074887-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10166771. Licensed CC0.

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