LADD syndrome is caused by mutations that reduce the tyrosine kinase activity of FGFR2. E. Rohmann^{1, 2}, I. Lax³, E.D. Lew³, V.P. Eswarakumar³, H.G. Brunner⁴, Y. Li^{1, 2}, H. Kayserili⁵, J. Schlessinger³, B. Wollnik^{1, 2}. 1) Center for Molecular Medicine Cologne (CMMC), Cologne, Germany; 2) Institute of Human Genetics, University of Cologne, Cologne, Germany; 3) Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA; 4) Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; 5) Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
   Lacrimo-auriculo-dento-digital (LADD) syndrome is an autosomal dominant disorder mainly affecting the lacrimal system, the ear-shape and hearing, teeth development, and digit patterning. We recently identified the molecular basis of LADD syndrome and found heterozygous missense mutations in LADD families in FGFR2, and FGFR3, and FGF10, one of FGFR2 ligands. Notably, the mutations in the FGF-receptor molecules were located in regulatory regions of the tyrosine kinase domain of the receptors. Previous studies have shown that different craniosynostosis syndromes are caused by gain-of-function mutations in FGFR2 which result in elevated tyrosine kinase activity of FGFR2. We have compared the tyrosine kinase activity of three LADD FGFR2 mutations and demonstrated that their intrinsic tyrosine kinase activity is reduced as compared to the tyrosine kinase activity of wild type FGFR2 or to the constitutively activated tyrosine kinase activity of FGFR2 mutant responsible for Pfeiffer syndrome. Furthermore, stimulation with a LADD FGF10 mutant protein led to a decreased FGFR2 activation and to compromised MAPK stimulation as compared to stimulation of these responses induced by wild type FGF10. We conclude that FGFR2- and FGF10-LADD mutations lead to reduced FGFR2 autophosphorylation and diminished cell signaling via FGFR2 and that the reduced tyrosine kinase activity of FGFR2 is a hallmark underlying the molecular basis of LADD syndrome.