# Defining Defects in Myosin Structure and Function That Cause Dominant Spondylocarpotarsal Synostosis

> **NIH NIH R21** · SAN DIEGO STATE UNIVERSITY · 2020 · $198,660

## Abstract

PROJECT SUMMARY
We propose to build and analyze the first animal models of dominant spondylocarpotarsal synostosis (SCT), a
human genetic disease that arises from mutations in the MYH3 embryonic myosin heavy chain. These
mutations yield misshaped and fused vertebral bodies as well as carpal and tarsal abnormalities that are
hypothesized to arise from primary defects in muscle function. Our transgenic Drosophila melanogaster
models will be used to dissect the biochemical, biophysical, developmental and physiological bases of this
disease. The Drosophila system will allow us to mutate the Drosophila myosin gene to examine the effects of
two SCT alleles in a standardized genetic background. This will define the importance of interactions between
wild-type and mutant myosin molecules to disease pathology and will obviate genetic heterogeneity that leads
to phenotypic variability in the human disease. Further we will explore the use of our transgenic system to
produce adequate quantities of human wild-type and SCT MYH3 to determine their functional properties and
solve their high-resolution crystal structures. We will test the following hypotheses: that actin binding, which
influences nucleotide affinity and filament motility, is abnormal in the SCT mutant myosin models; that
functionally abnormal SCT myosin leads to myofibril disruption and muscle dysfunction in the Drosophila
model; that structure-function relationships about human myosin can be discerned using our Drosophila-based
myosin expression system. To evaluate these hypotheses, we will pursue the following specific aims: 1)
Assess the ATPase, actin binding and actin motility capabilities of mutant SCT myosins compared to the wild-
type protein. 2) Determine the dominant effects of the mutations on myofibrillar ultrastructure and function of
muscles from the larval body wall and adult thorax (indirect flight and jump muscles). 3) Explore the possibility
of producing, isolating and determining the structural and functional properties of normal and SCT human
MYH3 protein using a unique indirect flight muscle expression system. This multifaceted approach will provide
mechanistic insights into the molecular and developmental bases of SCT and begin to elucidate how mutations
in a skeletal muscle protein lead to developmental defects in associated skeletal elements. Understanding the
underlying muscle defects causative of the disease may ultimately yield therapeutic approaches.

## Key facts

- **NIH application ID:** 9899926
- **Project number:** 5R21AR074407-02
- **Recipient organization:** SAN DIEGO STATE UNIVERSITY
- **Principal Investigator:** Sanford I Bernstein
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $198,660
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899926

## Citation

> US National Institutes of Health, RePORTER application 9899926, Defining Defects in Myosin Structure and Function That Cause Dominant Spondylocarpotarsal Synostosis (5R21AR074407-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9899926. Licensed CC0.

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