Rat neurological disease creeping is caused by a mutation in the reelin gene

Reelin (Reln) is an extracellular matrix protein secreted from distinct neuronal populations and controls neural cell positioning during brain development. Alterations of human RELN have been reported in two pedigrees with an autosomal recessive lissencephaly. Although several alleles of the mouse reeler mutation were identified as disruptions of Reln, there is no other animal model with a confirmed mutation in Reln. We recently established the Komeda Zucker creeping (KZC) rat strain with an autosomal recessive mutation creeping (cre), showing a reeler-like phenotype. We also found that creeping was located in the genomic segment on rat chromosome 4 containing Reln and that the expression level of Reln mRNA was markedly reduced in cre/cre homozygous mutant animals. Here we report positional candidate cloning of creeping, and identify a nucleotide insertion mutation in Reln. This mutation leads to a translational frameshift and results in truncation of the predicted protein in the fourth reelin-specific repeat, removing the C-terminal region required for secretion and function of the protein. We conclude that the mutation detected here is causative and is probably a null allele. The KZC rat is the first rat model with a confirmed Reln mutation and would therefore contribute to the understanding of the Reln function.