title: Identification of a 31-bp deletion in the RELN gene causing lissencephaly with cerebellar hypoplasia in sheep.
abstract: Lissencephaly is an inherited developmental disorder in which neuronal migration is impaired. A type of lissencephaly associated with cerebellar hypoplasia (LCH) was diagnosed in a commercial flock of Spanish Churra sheep. The genotyping of 7 affected animals and 33 controls with the OvineSNP50 BeadChip enabled the localization of the causative mutation for ovine LCH to a 4.8-Mb interval on sheep chromosome 4 using genome-wide association and homozygosity mapping. The RELN gene, which is located within this interval, was considered a strong positional and functional candidate because it plays critical roles in neuronal migration and layer formation. By performing a sequencing analysis of this gene's specific mRNA in a control lamb, we obtained the complete CDS of the ovine RELN gene. The cDNA sequence from an LCH-affected lamb revealed a deletion of 31 bp (c.5410_5440del) in predicted exon 36 of RELN, resulting in a premature termination codon. A functional analysis of this mutation revealed decreased levels of RELN mRNA and a lack of reelin protein in the brain cortex and blood of affected lambs. This mutation showed a complete concordance with the Mendelian recessive pattern of inheritance observed for the disease. The identification of the causal mutation of LCH in Churra sheep will facilitate the implementation of gene-assisted selection to detect heterozygous mutants, which will help breeders avoid at-risk matings in their flocks. Moreover, the identification of this naturally occurring RELN mutation provides an opportunity to use Churra sheep as a genetically characterized large animal model for the study of reelin functions in the developing and mature brain.
authors.affiliation: Dpto. Producción Animal, Universidad de León, León, León, Spain.
authors.forename: Aroa
authors.initials: A
authors.lastname: Suárez-Vega
authors.forename: Beatriz
authors.initials: B
authors.lastname: Gutiérrez-Gil
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Cuchillo-Ibáñez
authors.forename: Javier
authors.initials: J
authors.lastname: Sáez-Valero
authors.forename: Valentín
authors.initials: V
authors.lastname: Pérez
authors.forename: Elsa
authors.initials: E
authors.lastname: García-Gámez
authors.forename: Julio
authors.initials: J
authors.lastname: Benavides
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Arranz
mesh_terms: D000818:Animals; D001483:Base Sequence; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D002531:Cerebellum / Q000002:abnormalities* / Q000473:pathology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D033481:Chromosomes, Mammalian; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000150:complications / Q000235:genetics / Q000473:pathology; D005091:Exons; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D055106:Genome-Wide Association Study; D054082:Lissencephaly / Q000150:complications / Q000235:genetics* / Q000473:pathology; D008297:Male; D023421:Models, Animal; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009421:Nervous System Malformations / Q000150:complications / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics*; D000091042:Reelin Protein; D017384:Sequence Deletion; D012697:Serine Endopeptidases / Q000235:genetics*; D034561:Sheep, Domestic
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D018389:Codon, Nonsense; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D000091042:Reelin Protein; D012697:Serine Endopeptidases