Lacrimo-auriculo-dento-digital (LADD) syndrome, also known as Levy-Hollister syndrome, is a rare autosomal dominant developmental disorder, mainly characterized by abnormalities of the lacrimal system and salivary glands, ears and hearing, teeth and distal limb development. Besides these cardinal features, facial dysmorphism and malformations of the kidney and the respiratory system have been reported. In this study, the LADD1 locus was mapped to chromosome 10q26 by genome wide linkage analysis using the Affymetrix GeneChip 10K array in three large LADD families. In all three LADD families and in one sporadic case, heterozygous missense mutations were found in exon 16 of the gene encoding the fibroblast-growth-factor-receptor 2 (FGFR2). After exclusion of the FGFR2 locus by haplotype analysis in two additional LADD families, one missense mutation was identified in FGFR3 and one mutation was found in the fibroblast-growth-factor 10 (FGF10), a known ligand of FGFR2 [Rohmann et al., 2006]. The functional properties of FGF10 LADD and FGFR2 LADD mutants were analyzed and compared to the activities of their normal counterparts. Protein expression in BL21 cells and binding studies showed that each of the three analyzed FGF10 mutations demonstrated severely impaired activity by different mechanisms. Transient and stable expression studies exhibited that the FGFR2 mutations possess a reduced autophosphorylation and a weaker tyrosine kinase activity. Mutations also lead to diminished phosphorylation activity in FGFR2-mediated substrates (e. g. FRS2 and Shc) and to a decreased downstream signaling pathway, as shown by MAPK activity. While tested FGF10 LADD mutations caused haploinsufficiency, the FGFR2 LADD mutants could exert a dominant-negative effect on normal FGFR2 protein [Shams and Rohmann et al., 2007]. An in vitro kinase assay and crystallization of both, FGFR2 WT and the p.A628T missense mutation in the catalytic part of the tyrosine kinase domain, demonstrated that the A628T LADD mutation disrupts the catalytic activity due to conformational changes, leading to LADD syndrome. In addition, the newly described crystal structure of FGFR2 in comparison to FGFR1 revealed that the FGFR2 utilizes a less stringent mode of autoinhibition [Lew, Bae and Rohmann et al., 2007]
