Three novel SALL1 mutations extend the mutational spectrum in Townes-Brocks syndrome. J. Kohlhase¹, C. Blanck¹, S. Engels¹, P. Burfeind¹, A. Bottani², M. Patel³, W. Engel¹, H.Y. Kroes⁴, J.M. Cobben⁴. 1) Institute for Human Genetics, University of Goettingen, Goettingen, Germany; 2) Division of Medical Genetics, University of Geneva, Geneva, Switzerland; 3) Department of Genetics, The Hospital for Sick Children, Toronto, ON, Canada; 4) Department of Medical Genetics, University of Groningen, Groningen, The Netherlands.

   Townes-Brocks syndrome (TBS) is an autosomal dominantly inherited malformation syndrome characterized by anal, renal, limb, and ear anomalies. TBS is caused by mutations in the putative zinc finger transcription factor gene SALL1 related to spalt of Drosophila. All mutations identified so far are truncating mutations (nonsense mutations or short deletions), which are located 5' of the first double zinc finger encoding region. This led to the suggestion that only SALL1 mutations which remove all double zinc finger domains result in TBS. Here we present three novel mutations of SALL1, one single base pair deletion, one nonsense mutation, and one intronic mutation. While the short deletion is located within the previously described hotspot region, the nonsense mutation is positioned 3' of the region encoding the first double zinc finger. The intronic mutation creates a aberrant splice site and is predicted to result in a protein in which all but the most carboxyterminal zinc finger domains are intact. Based on these findings, we suggest that all double zinc finger domains of SALL1 are required for SALL1 function, and that truncating mutations removing one or more of these domains from the SALL1 protein result in the same phenotype.