Irfan Saadi, MS, PhD

Dr. Irfan Saadi received his B.Sc. (Hon.) and M.Sc. degrees in Biology from McGill University in Montreal, Canada, where he began his research career in Dr. Rima Rozen’s laboratory working on genotype-phenotype correlation in patients with cystinuria. He earned his Ph.D. in Genetics from the University of Iowa in Dr. Andrew Russo’s laboratory studying the molecular consequences of disease-causing mutations in Axenfeld-Rieger syndrome. His postdoctoral training at Harvard was in genetic analyses of palate and tooth development with Dr. Richard Maas, a preeminent scholar of craniofacial morphogenesis. Dr. Saadi joined the University of Kansas Medical Center in 2011 as an Assistant Professor. He is currently an Associate Professor with Tenure in the Department of Cell Biology and Physiology. His research is focused on understanding the molecular mechanisms underlying embryonic morphogenesis and congenital anomalies.

Craniofacial malformations afflict about 5% of all infants born in the United States and comprise approximately one-third of all birth defects. While a number of contributory genes have been identified, they account for only a subset of cases at best. Thus, there is continued need to identify additional genes and to understand underlying pathogenetic mechanisms. We are currently investigating the role of a novel cytoskeletal protein, SPECC1L, in craniofacial morphogenesis and malformation.

To explore the role of SPECC1L, we are using four broad approaches: 1) Human Genetics – we continue to collaborate with clinicians nationally to identify SPECC1L mutations in patients with syndromic and isolated orofacial clefting [Saadi, 2011; Kruszka, 2015]. 2) Mouse Models – we have now generated an allelic series of Specc1l mutants, including knockout, hypomorphic, and point mutants. These alleles allow us to vary Specc1l dosage, which results in an array of phenotypes, including embryonic lethality, cleft palate, exencephaly, hydrocephalus and behavioral deficits. 3) Cell Biology – we have shown that SPECC1L regulates the density of cell-cell contacts in pre-migratory neural crest cells resulting in defective delamination in severe mutants [Wilson, 2016]. We are using live-cell imaging to show that SPECC1L also regulates cell-cell communication required for collective migration of neural crest cells in hypomorphic and point mutants. 4) Molecular Biology – we have shown that SPECC1L is a novel regulator of PI3K-AKT signaling. We are now using RNA-seq and protein-protein interactions to show how SPECC1L regulates the stability of AKT and other signaling molecules.

Understanding the role of SPECC1L will provide i) valuable insights into modulation of cell-cell contacts and cell adhesion during craniofacial morphogenesis, ii) a novel network of genes that may be involved in craniofacial malformation, and iii) potential therapeutic targets for orofacial clefting.

Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting.

Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia.

In-frame deletion of SPECC1L microtubule association domain results in gain-of-function phenotypes affecting embryonic tissue movement and fusion events.

In-frame deletion of SPECC1L microtubule association domain results in gain-of-function phenotypes affecting embryonic tissue movement and fusion events.

In-frame deletion of SPECC1L microtubule binding domain results in embryonic tissue movement and fusion defects.

Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud-to-cap stage transition in tooth development.

Mutations in the RNA Granule Component TDRD7 Cause Cataract and Glaucoma

SPECC1L deficiency results in increased adherens junction stability and reduced cranial neural crest cell delamination.

SPECC1L regulates palate development downstream of IRF6

SPECC1L-deficient primary mouse embryonic palatal mesenchyme cells show speed and directionality defects.

SUMO1 haploinsufficiency leads to cleft lip and palate.

Role of SPECC1L-AKT Axis in Neural Tube Closure

The Role of SPECC1L cytoskelatal protein in craniofacial development and malformation