# The molecular pathophysiology of the congenital dyserythropoietic anemias

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $614,718

## Abstract

Project Summary
Anemia due to defects in erythropoiesis (red blood cell [RBC] production) is a major source of mortality and
morbidity worldwide. The Congenital Dyserythropoietic Anemias (CDAs) are a group of disorders of terminal
erythroid maturation defects characterized by ineffective erythropoiesis and distinctive bone marrow (BM) find-
ings. CDAII is the most common CDA subtype, followed by CDAI. CDAII is an autosomal recessive disease
resulting from loss-of-function mutations in SEC23B, encoding a core component of coat protein complex-2
(COPII) vesicles, which transport secretory proteins from the Endoplasmic reticulum (ER) to the Golgi appa-
ratus. CDAI, also an autosomal recessive disease, results from loss-of-function mutations in CDAN1, encoding
CODANIN1, which is proposed to play a role in chromatin assembly. Despite the identification of the genetic
defects underlying CDAI and CDAII, the pathophysiology of these disorders remains unknown. CODANIN1 has
been shown to co-localize intracellularly with SEC23B, suggesting that CDAI and CDAII might share a com-
mon or related molecular pathogenesis. We previously generated mice with hematopoietic SEC23B deficiency;
these mice did not exhibit a RBC defect. We next showed through studies in yeast, zebrafish, mice, and hu-
man cells that SEC23B overlaps in function with its closely related paralog, SEC23A, and that the expression
pattern of the SEC23 paralogs has shifted in evolution (SEC23B is the predominantly expressed paralog in
human BM, with comparable SEC23A and SEC23B levels in mouse BM). The overall objective of this proposal
is to characterize the molecular pathogenesis of the CDAs. In early preliminary results, i) we generated mice
with erythroid-specific combined Sec23a/Sec23b deletion; these mice exhibit a profound erythroid phenotype;
ii) we also generated mice with hematopoietic Cdan1 deletion, which demonstrate a profound hematologic de-
fect. In this proposal, we aim to characterize the critical roles of CODANIN1 and SEC23 in erythropoiesis and
define the extent of the hematopoietic defect resulting from Cdan1 or combined Sec23a/Sec23b deletion. We
also aim to define the genetic interaction between Sec23b and Cdan1 in vivo and determine the intracellular
trafficking of CODANIN1 in SEC23B-deficient versus wild-type erythroid cells. Furthermore, based on the ER-
to-Golgi transport defect in CDAII and on the lysis of CDAII RBC in some acidified human sera, which suggests
an RBC membrane abnormality, we hypothesize that CDAII results from impaired trafficking of one or more
key cargo proteins to the RBC plasma membrane. In preliminary results we demonstrate significant depletion
of only 5 proteins in CDAII compared to control RBC plasma membranes. We will expand our studies by defin-
ing the secretion of these cargos in additional CDAII patient samples and we will identify the roles of these car-
gos in the pathophysiology of CDAII. Our proposed studies have important implications...

## Key facts

- **NIH application ID:** 10165812
- **Project number:** 5R01HL148333-03
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Rami Khoriaty
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $614,718
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165812

## Citation

> US National Institutes of Health, RePORTER application 10165812, The molecular pathophysiology of the congenital dyserythropoietic anemias (5R01HL148333-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10165812. Licensed CC0.

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