The gene encoding disabled-1 (DAB1), the intracellular adaptor of the Reelin pathway, reveals unusual complexity in human and mouse

The Disabled-1 (Dab1) gene encodes a key regulator of Reelin signaling. Reelin is a large glycoprotein secreted by neurons of the developing brain, particularly Cajal-Retzius cells. The DAB1 protein docks to the intracellular part of the Reelin very low density lipoprotein receptor and apoE receptor type 2 and becomes tyrosine-phosphorylated following binding of Reelin to cortical neurons. In mice, mutations of Dab1 and Reelin generate identical phenotypes. In humans, Reelin mutations are associated with brain malformations and mental retardation; mutations in DAB1 have not been identified. Here, we define the organization of Dab1, which is similar in human and mouse. The Dab1 gene spreads over 1100 kb of genomic DNA and is composed of 14 exons encoding the major protein form, some alternative internal exons, and multiple 5′-exons. Alternative polyadenylation and splicing events generate DAB1 isoforms. Several 5′-untranslated regions (UTRs) correspond to different promoters. Two 5′-UTRs (1A and 1B) are predominantly used in the developing brain. 5′-UTR 1B is composed of 10 small exons spread over 800 kb. With a genomic length of 1.1 Mbp for a coding region of 5.5 kb, Dab1 provides a rare example of genomic complexity, which will impede the identification of human mutations.