Abstrakt
Zimmermann-Laband syndrome (ZLS) is a rare autosomal dominant disorder, the genetic basis of which has not been identified thus far. We previously mapped the breakpoints of two different translocations in patients with ZLS to a common region in 3p14.3; however, we failed to detect mutations in genes located in a region surrounding both breakpoints as well as in those of another breakpoint region (8q24.3) (Abo-Dalo et al., 2007).
The WNT5A gene is located proximal to both breakpoints in 3p14.3, with a distance of around 550 kb or less, making it likely that a position effect may cause deregulated expression of WNT5A. This gene codes for a secreted glycoprotein that belongs to a family of signaling molecules involved in multiple developmental processes, such as hair follicle morphogenesis and limb outgrowth (Yamaguchi et al., 1999; Reddy et al., 2001) these are processes that are obviously altered in patients with ZLS.
Signaling via Wnt molecules, such as Wnt5a, is mediated by two classes of receptors, frizzled receptors (FZD 2, 4, 5, and 7) and the receptor tyrosine kinase Ror2 (Mikels and Nusse, 2006), and can be antagonized by Dickkopf (Dkk) proteins 1-4 (Kawano and Kypta, 2003). Mutations in ROR2 cause brachydactyly type B (MIM 113000) and Robinow syndrome (MIM 268310) (Kornak and Mundlos, 2003).
Both disorders are characterized by skeletal malformations and show partial phenotypic overlap with ZLS, for example hypoplasia of distal phalanges. On the basis of these data we wanted to explore the possibility that mutations of WNT5A or other genes encoding molecules involved in WNT5A-dependent signaling pathways cause ZLS.