Department of Anatomy and Cell Biology
Ph.D., The University of Iowa, 2003
Postdoctoral, Brigham and Women's Hospital, Harvard Medical School, 2003-2009
Postdoctoral, The Forsyth Institute, 2009-2011
Craniofacial malformations afflict about 5% of all infants born in the United States and comprise approximately one third of all birth defects. These anomalies result in significant medical, social and economic consequences. Orofacial clefts are one such common congenital facial defect that affects 1/800 live births. Cleft lip with or without cleft palate (CL/P) comprises the majority of orofacial clefts. The Center for Disease Control and Prevention (CDC) estimates that the lifetime cost for treating kids born each year with CL/P is over US$697 million. Our goal is to understand the pathogenetic mechanisms of craniofacial birth defects. We identified SPECC1L as the first gene mutated in a severe cleft that extends from the oral cavity to the eye, termed Oblique Facial Cleft (ObFC) [Saadi, AJHG 2011]. We proposed that cellular and molecular mechanisms underlying ObFC and SPECC1L function are directly related to common CF malformations, including CL/P. Indeed, new SPECC1L mutations have been identified in patients with syndromic CL/P [Kruszka, JMG 2015], underscoring the need to investigate the role of this novel cytoskeletal protein.
Homozygous Specc1l gene-trap mutants die during early embryogenesis with defects in neural tube (NT) closure and delamination/migration of cranial neural crest cells (CNCCs). Further, SPECC1L-deficient cells show altered adherens junction (AJ) staining predicted to reflect more dense AJs [Wilson, SciRep 2016], which leads to not only poor delamination of CNCCs, but also affects cell migration. Interestingly, live-imaging analysis indicates that the migration defect is not due to slower individual speed, but rather due to poor collective movement. Together, these data begin to provide a genetic basis for orofacial clefting and implicate defective SPECC1L-mediated cell adhesion and migration as a novel underlying mechanism.
Wilson NR, Olm-Shipman AJ, Acevedo DS, Palaniyandi K, Hall E, Kosa E, Stumpff KM, Smith GJ, Pitstick L, Liao EC, Bjork BC, Czirok A, Saadi I. SPECC1L deficiency results in increased adherens junction stability and reduced cranial neural crest cell delamination. Scientific Reports. 2016 Jan 20; 6:17735
Kruszka P, Li D, Harr MH, Wilson NR, Swarr D, McCormick EM, Chiavacci RM, Li M, Martinez AF, Hart RA, McDonald-McGinn DM, Deardorff MA, Falk MJ, Allanson JE, Hudson C, Johnson JP, Saadi I, Hakonarson H, Muenke M, Zackai EH. Mutations in SPECC1L, encoding sperm antigen with calponin homology and coiled-coil domains 1-like, are found in some cases of autosomal dominant Opitz G/BBB syndrome. J Med Genet. 2015 Feb;52(2):104-10.
Saadi I, Das P, Zhao M, Raj L, Ruspita I, Xia Y, Papaiooannou VE and Bei M (2013) Msx1 and Tbx2 antagonistically regulate Bmp4 expression during bud to cap stage transition during tooth development. Development 140:2697-702.
Saadi I*, Alkuraya FS*, Gisselbrecht SS, Goessling W, Cavallesco R, Turbe-Doan A, Petrin AL, Harris J, Siddiqui U, Grix AW Jr, Hove HD, Leboulch P, Glover TW, Morton CC, Richieri-Costa A, Murray JC, Erickson RP, Maas RL. Deficiency of the cytoskeletal protein SPECC1L leads to oblique facial clefting. Am J Hum Genet. 2011 Jul 15;89(1):44-55.
Irfan Saadi, Ph.D.