# Pathogenesis of craniofacial defects in Nager syndrome

> **NIH NIH R01** · NEW YORK UNIVERSITY · 2020 · $396,250

## Abstract

PROJECT SUMMARY/ABSTRACT
Mandibulofacial dysostosis (MFD) is a developmental disorder characterized by hypoplasia of neural crest-
derived craniofacial bones, particularly the maxilla, mandible, and zygomatic complex, as well as malformation
of the outer ears and middle ear ossicles. It is the second most frequent craniofacial malformation after cleft lip
and palate. Nager syndrome combines many features of MFD with a variety of limb defects, typically
hypoplasia or absence of the thumbs. Mutations in SF3B4 (splicing factor 3b, subunit 4), a component of the
pre-mRNA spliceosomal complex located on chromosome 1, were recently identified as a cause for Nager
syndrome, accounting for approximately 60% of the cases. Interestingly, mutations in others component of the
spliceosome, EFTUD2 and SNRPB, also cause MFD in two related but distinct syndromes known as
mandibulofacial dysostosis with microcephaly and cerebro-costo-mandibular syndrome, respectively,
suggesting that mutations in components of the spliceosome may underlie the etiology of MFD. The proposed
experiments will test the hypothesis that components of the spliceosomal complex are required for neural crest
progenitors formation and cause MFD when their function is altered. We have designed three specific aims to
specifically address this question. (1) We will characterize the molecular mechanisms underlying MFD in Nager
syndrome, by analyzing neural crest development in Sf3b4-depleted Xenopus embryos using morpholino
antisense oligonucleotides and the CRISPR/Cas9 genome editing technology. We will ask whether the
expression of neural crest specific genes and the pattern of cell proliferation and apoptosis are affected in
these embryos. (2) We will characterize the pre-mRNA splicing activity of Sf3b4 by RNA-seq to identify
transcripts that show intron retention in Sf3b4-depleted embryos, and determine whether these transcripts
encode factors important for neural crest formation. (3) A region of chromosome 9 (9q32) has also been linked
to Nager syndrome. This region contains two genes involved in pre-mRNA processing, PRPF4 (pre-mRNA
processing factor 4) and PTBP3 (Polypyrimidine tract binding protein 3). We will analyze the function of these
genes and determine their possible involvement in neural crest and craniofacial development, as potential
novel candidate genes for Nager syndrome. The studies proposed in this application will identify and
characterize genes critically required for neural crest and craniofacial development, and will provide important
novel insights into the etiology and pathogenesis of Nager syndrome.

## Key facts

- **NIH application ID:** 9875269
- **Project number:** 5R01DE025468-05
- **Recipient organization:** NEW YORK UNIVERSITY
- **Principal Investigator:** Jean-Pierre Saint-Jeannet
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2016-07-01 → 2022-02-27

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9875269

## Citation

> US National Institutes of Health, RePORTER application 9875269, Pathogenesis of craniofacial defects in Nager syndrome (5R01DE025468-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9875269. Licensed CC0.

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