# Novel Mechanisms of Congenital Dyserythropoietic Anemia

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $31,976

## Abstract

Abstract
The congenital dyserythropoietic anemias (CDAs) are a heterogeneous group of genetic diseases of red blood
cell production marked by hyporegenerative anemia with the presence of multinucleated red blood cell
precursors in the bone marrow. Numerous gene loci have been associated with CDA, the most common being
codanin-1 (CDAI) and SEC23B (CDA II). Although a common cause of CDA worldwide, the function of
codanin-1 is largely unknown. We have demonstrated that codanin-1 is a chromatin binding protein whose
expression is maintained during erythroid differentiation. The objective of this application is to identify the
function of CDA-associated proteins in erythropoiesis, with a particular focus on codanin-1 and a newly
identified CDA protein, MACF1. This will be explored by examining three Specific Aims: (1) study of
mechanisms of codanin-1 regulation of gene expression during erythropoiesis; (2) characterization of a murine
CRISPR/Cas9 knockin model of a codanin-1 CDA- associated point mutations; and (3) characterization of the
role of MACF1 in erythropoiesis and in the pathophysiology of CDA, including development of a knockin and
knockout mutant MACF1-linked murine model of CDA. The central hypothesis is that codanin-1 and MACF1
are involved in regulation of erythroid development and differentiation. The experimental plan focuses on
understanding this regulation using cell lines, human and murine primary erythroid cell systems, and mouse
models. Preliminary data support the hypotheses and proposed studies. Diminished expression of codanin-1 in
CDA I by siRNA and overexpression of a patient-derived point mutant codanin-1 both result in erythroid
precursor multinuclearity and decreased hemoglobinization. Genetic analyses strongly support the role of
MACF1 in CDA. The investigators have created numerous important tools for the proposed studies. The
rationale for this proposal is that by understanding the pathophysiology of a rare disease like CDA, we will gain
broad knowledge of mechanisms controlling erythropoiesis, resulting in insights applicable to development of
therapeutic strategies for inherited and acquired disorders of red blood cell production. This project takes
advantage of a wealth of expertise using the multiple PI format, joining 2 experienced hematologic researchers
in Pediatrics at Yale. Dr. Gallagher has experience studying mechanisms of erythropoiesis and its perturbation
in genetic disease as well as genomics of erythroid development and differentiation. Dr. Kupfer has studied
fundamental aspects of hematopoiesis and its perturbation using Fanconi anemia as a model. Together these
investigators are uniquely qualified to study diseases associated with dysfunctional erythropoiesis. The co-PIs
are actively involved in molecular hematology research at Yale; both are co-PIs of the Yale Cooperative Center
of Excellence in Hematology (YCCEH), providing support for some of the studies in this proposal. Together,
these studies w...

## Key facts

- **NIH application ID:** 10690641
- **Project number:** 5R01DK111539-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** PATRICK G GALLAGHER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $31,976
- **Award type:** 5
- **Project period:** 2020-09-01 → 2023-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690641

## Citation

> US National Institutes of Health, RePORTER application 10690641, Novel Mechanisms of Congenital Dyserythropoietic Anemia (5R01DK111539-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10690641. Licensed CC0.

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