title: Rat neurological disease creeping is caused by a mutation in the reelin gene.
abstract: 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.
authors.affiliation: Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University, Chiba, 260-8670, Japan. yokio@med.m.chiba-u.ac.jp
authors.forename: Norihide
authors.initials: N
authors.lastname: Yokoi
authors.forename: Misako
authors.initials: M
authors.lastname: Namae
authors.forename: He-Yao
authors.initials: HY
authors.lastname: Wang
authors.forename: Ken
authors.initials: K
authors.lastname: Kojima
authors.forename: Masanori
authors.initials: M
authors.lastname: Fuse
authors.forename: Kazuki
authors.initials: K
authors.lastname: Yasuda
authors.forename: Tadao
authors.initials: T
authors.lastname: Serikawa
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
authors.forename: Kajuro
authors.initials: K
authors.lastname: Komeda
mesh_terms: D000818:Animals; D001483:Base Sequence / Q000235:genetics; D001921:Brain / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D015816:Cell Adhesion Molecules, Neuronal / Q000172:deficiency* / Q000235:genetics / Q000302:isolation & purification; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D018389:Codon, Nonsense / Q000235:genetics; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics; D016326:Extracellular Matrix Proteins / Q000172:deficiency* / Q000235:genetics / Q000302:isolation & purification; D005838:Genotype; D008969:Molecular Sequence Data; D009069:Movement Disorders / Q000235:genetics* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D010641:Phenotype; D051381:Rats; D011919:Rats, Inbred Strains; D000091042:Reelin Protein; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D012697:Serine Endopeptidases
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D018389:Codon, Nonsense; D018076:DNA, Complementary; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717129:Reln protein, rat; C000717127:RELN protein, human; C000717128:Reln protein, mouse; D012697:Serine Endopeptidases