# A genetic and molecular approach to understanding allelic and phenotypic heterogeneity in Acrofacial dysostosis, Cincinnati-type

> **NIH NIH K08** · CINCINNATI CHILDRENS HOSP MED CTR · 2021 · $162,980

## Abstract

ABSTRACT
Congenital heart defects (CHD) are the most common class of birth defects, with a prevalence of approximately
1% of live births and a wide range of morbidity and mortality. Disorders of ribosome biogenesis
(“ribosomopathies”) are congenital malformation syndromes variably associated with both CHD and craniofacial
anomalies. The mechanism by which disruption of a ubiquitous process (ribosome biogenesis) leads to tissue-
specific phenotypes such as CHD is unknown. Acrofacial dysostosis, Cincinnati type (AFD-CIN) is a recently
identified autosomal dominant ribosomopathy caused by mutations in POLR1A. Among our cohort of patients
with AFD-CIN we observed an increased incidence of CHD. The objective of this application is to study how
POLR1A-mediated perturbation of ribosome biogenesis disrupts cardiac development, and to determine the
mechanisms underlying tissue-specific effects of different POLR1A alleles. The central hypothesis is that distinct
POLR1A alleles cause lineage-specific alteration of translational regulation of protein expression. We will test
this hypothesis with the following three specific aims: [1] Analyze the requirement for Polr1a in neural crest cells
and the second heart field, [2] Analyze phenotype and function of an allelic series of Polr1a, and [3] Quantify
the lineage-specific effects of distinct Polr1a alleles on ribosome biogenesis and mRNA translation. Methods will
include [1] detailed phenotyping of conditional knock-out alleles of Polr1a, [2] generating in vitro and in vivo
(mouse) models of human mutations, and [3] assessing tissue-specific effects of Polr1a disruption with RNA-seq
and Ribo-Seq. Through completion of these three aims, I will gain experience and skills as an independent
investigator leading clinical, translational, and basic research. Successful completion of the goals of this grant
will [1] define a role for ribosome biogenesis in cardiac development, [2] confirm pathogenicity of POLR1A
genetic variants in mice, [3] provide insight into pathogenic domains of POLR1A, and [4] elucidate novel
pathways that mediate tissue-specific phenotypes associated with loss of Polr1a. Collectively this could enable
intervention to reduce severity or even prevent malformations associated with defects in ribosome biogenesis.

## Key facts

- **NIH application ID:** 10146464
- **Project number:** 5K08HL143177-03
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Kathryn Nicole Weaver
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $162,980
- **Award type:** 5
- **Project period:** 2019-04-11 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146464

## Citation

> US National Institutes of Health, RePORTER application 10146464, A genetic and molecular approach to understanding allelic and phenotypic heterogeneity in Acrofacial dysostosis, Cincinnati-type (5K08HL143177-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10146464. Licensed CC0.

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