Irfan Saadi, PhD

Assistant Professor
Anatomy and Cell Biology
Institute for Reproductive Health and Regenerative Medicine
Kansas Intellectual and Developmental Disabilities Research Center

PhD: 2003, The University of Iowa, Iowa City, IA
Postdoctoral Fellow: Brigham and Women’s Hospital, Harvard Medical School, Boston, MA
Postdoctoral Fellow: The Forsyth Institute, Cambridge, MA


Publications: PubMed

Research

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 and non-syndromic CL/P, 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 neural crest cells (NCCs). Further, SPECC1L-deficient cells show altered adherens junction (AJ) staining predicted to reflect more dense AJs, which leads to poor 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 migration and adhesion as a novel underlying mechanism.

THM1 (green) localizes in a punctate fashion from base to tip of cilium.  Tubulin (red) marks the ciliary core or axoneme.SPECC1L Mutations in Patients with Orofacial Clefts. (a) Tessier IV type cleft in the patient with SPECC1L Q415P mutation. Schematic representation of SPECC1L protein showing position of the de novo heterozygous Q415P (p.Gln415Pro) missense mutation identified in a second patient with Oblique Facial Clefts [Saadi, 2011]. Also shown is a new missense mutation (p.Thr397Pro) identified in a family with affecteds showing hypertelorism and bilateral cleft lip and palate (Dr. Zackai, CHOP collaboration). The p.Met91Ile and p.Arg546Gln changes were identified in two patients with non-syndromic cleft lip/palate (Dr. Murray, U. Iowa)

Saadi Detail

Specc1l deficiency leads to impaired NCC function. A-D) E9.5 WT and mutant embryos with neural crest cells (NCCs) marked with Wnt1-Cre. The Specc1l mutant embryo shows an open neural folds with NCCs that have still not migrated (arrows). E-H) Brightfield (E,G) and NCC marker DLX2 immunostain (F,H) of E10.5 WT (E,F) and Specc1lDTM096/DTM096 mutant (G,H) embryos. In E10.5 WT embryo, DLX2 positive NCCs populate the branchial arches (arrowhead), while in the mutant significant staining remains in open neural folds (C,D; arrows), indicating poor NCC delamination and/or migration.

Our Lab

Diana Acevedo

Diana Acevedo
Lab Manager

Nathan Wilson

Nathan Wilson
Graduate Student

Last modified: Jun 25, 2014

Irfan Saadi, PhD

Contact

Irfan Saadi, PhD
Assistant Professor
Anatomy and Cell Biology
Institute for Reproductive Health and Regenerative Medicine

HSLIC Room 2065, Mailstop 3051
3901 Rainbow Boulevard
Kansas City, KS 66160

P: 913-588-7667
F: 913-588-5677
isaadi@kumc.edu

ID=x4074