Research seeks to gain novel insights into the pathogenesis of Nager syndrome, a rare craniofacial disorder, and to identify novel candidate genes as potential causes of the disease, steps toward early detection, and reduction of craniofacial malformations at birth.

Dr. Jean-Pierre Saint-Jeannet

The National Institutes of Health (NIH) has awarded Jean-Pierre Saint-Jeannet, PhD, professor of basic science and craniofacial biology at NYU College of Dentistry, a five-year, $2M grant to develop an animal model to characterize the molecular mechanisms underlying the craniofacial defects observed in Nager syndrome patients, and to identify novel candidate genes as potential causes of the disease.

Nager syndrome is a rare craniofacial disorder characterized by underdeveloped cheek bones, undersized lower jaw, and cleft palate. These defects frequently cause feeding and breathing problems. Affected individuals also have hearing loss due to defects in the middle ear ossicles, as well as deformed outer ears and variable upper-limb defects. Mutations in the SF3B4 gene were recently identified as a cause of Nager syndrome, accounting for 60 percent of affected individuals. Most genes are transcribed as pre-mRNAs that contain intervening sequences (introns), as well as expressed sequences (exons). SF3B4 encodes a protein of the spliceosome, the cellular machinery that removes the introns and joins exons together to produce mature mRNAs, a process known as splicing.

“Interestingly,” says Professor Saint-Jeannet, “mutations in genes encoding other components of the spliceosome, EFTUD2 and SNRPB, cause similar craniofacial defects 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 craniofacial syndromes.”

Professor Saint-Jeannet and his team have generated the first animal model for Nager syndrome by specifically knocking down Sf3b4 function in the frog Xenopus Laevis. These animals have reduced craniofacial structures, reminiscent of the craniofacial defects seen in Nager syndrome patients. “With this tool,” says Professor Saint-Jeannet, “we are in a unique position to understand how mutations in this gene lead to craniofacial malformations.” They will ask three specific questions:

  1. What are the molecular mechanisms underlying craniofacial defects in Nager syndrome?
    The craniofacial bones affected in Nager syndrome are derived from a cell population in the early embryo known as the neural crest. The team found that in the absence of Sf3b4 function Xenopus embryos have a reduced number of neural crest progenitors. To determine the causes of this phenotype, they will analyze the expression of key neural crest regulators at different times during development and evaluate potential defects in neural crest specification, proliferation, and survival.
  2. What are the target genes of Sf3b4 pre-mRNA splicing activity?
    Because Sf3b4 is involved in pre-mRNAs splicing, it is reasonable to believe that the mRNAs processing of factors critical for neural crest formation may show aberrant splicing. To identify Sf3b4 targets, the team will analyze the global impact of Sf3b4 depletion on pre-mRNAs processing in the embryo. They will also evaluate other functions of Sf3b4 that do not involve splicing as a possible disease mechanism.
  3. Are other components of the spliceosome implicated in Nager syndrome?
    A region of chromosome 9 has been linked to Nager syndrome, and this region contains several genes involved in pre-mRNAs processing. The research team will test whether depletion of these genes in Xenopus embryos affect neural crest and craniofacial development in a manner comparable to Sf3b4 depletion.

“These studies,” says Professor Saint-Jeannet, will identify genes important for neural crest and craniofacial development, and will provide novel insights into the etiology and pathogenesis of Nager syndrome. The long term goals are to develop assays for early detection of the disease, and strategies to minimize craniofacial malformations at birth.”

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