# Functional and mechanistic characterization of YWHAZ variants associated with human diseases

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $571,030

## Abstract

Recent explosion in genomic medicine studies has led to identification of an increasing number of
genomic variations from patients with congenital defects. However, detailed analyses about how the
variants affect developmental processes are scarce, resulting in a growing class of variants classified
as variants of uncertain significance (VUS). Understanding functional consequences of VUS will help
patients, their families, and their doctors to learn genetic underpinnings of their conditions, enable
clinicians to provide personalized medical care and treatment, and expand our knowledge on biology
and mechanistic operations of the molecules involved in disease processes. In this proposal, we plan
to employ multidisciplinary approaches to investigate the YWHAZ variants associated with congenital
syndromes. Our preliminary studies on one variant identified from a patient with RASopathy revealed
that the variant activated the RAF-ERK pathway more efficiently than wild type YWHAZ in a vertebrate
animal model, the African clawed frog Xenopus. The results show for the first time that YWHAZ
variant may contribute to etiology of RASopathies. Several other YWHAZ variants also associate with
human disorders, but functional significance of the variants has not been examined. Our proposed
research will leverage the advantages of the Xenopus model, the power of biochemical and structural
studies, and the strength of the mouse genetic system for detailed characterization of the YWHAZ
variants. We will investigate whether and how YWHAZ variants have altered activities (aim 1), how
sequence variations affect protein structure and interaction (aim 2), and how the variants induce
pathology in the mouse models (aim 3). The novel combination of our investigation teams with
expertise in distinct research disciplines promises generation of profound insight into disease-
associated YWHAZ gene function and mechanisms.

## Key facts

- **NIH application ID:** 10136060
- **Project number:** 5R01HD102015-02
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** CHENBEI CHANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $571,030
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136060

## Citation

> US National Institutes of Health, RePORTER application 10136060, Functional and mechanistic characterization of YWHAZ variants associated with human diseases (5R01HD102015-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10136060. Licensed CC0.

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