title: A 20 bp Duplication in Exon 2 of the Aristaless-Like Homeobox 4 Gene (ALX4) Is the Candidate Causative Mutation for Tibial Hemimelia Syndrome in Galloway Cattle.
abstract: Aristaless-like homeobox 4 (ALX4) gene is an important transcription regulator in skull and limb development. In humans and mice ALX4 mutations or loss of function result in a number of skeletal and organ malformations, including polydactyly, tibial hemimelia, omphalocele, biparietal foramina, impaired mammary epithelial morphogenesis, alopecia, coronal craniosynostosis, hypertelorism, depressed nasal bridge and ridge, bifid nasal tip, hypogonadism, and body agenesis. Here we show that a complex skeletal malformation of the hind limb in Galloway cattle together with other developmental anomalies is a recessive autosomal disorder most likely caused by a duplication of 20 bp in exon 2 of the bovine ALX4 gene. A second duplication of 34 bp in exon 4 of the same gene has no known effect, although both duplications result in a frameshift and premature stop codon leading to a truncated protein. Genotyping of 1,688 Black/Red/Belted/Riggit Galloway (GA) and 289 White Galloway (WGA) cattle showed that the duplication in exon 2 has allele frequencies of 1% in GA and 6% in WGA and the duplication in exon 4 has frequencies of 23% in GA and 38% in WGA. Both duplications were not detected in 876 randomly selected German Holstein Friesian and 86 cattle of 21 other breeds. Hence, we have identified a candidate causative mutation for tibial hemimelia syndrome in Galloway cattle and selection against this mutation can be used to eliminate the mutant allele from the breed.
authors.affiliation: Institute of Veterinary Medicine, Georg-August-University of Göttingen, 37077 Göttingen, Germany.
authors.forename: Bertram
authors.initials: B
authors.lastname: Brenig
authors.affiliation: Institute of Veterinary Medicine, Georg-August-University of Göttingen, 37077 Göttingen, Germany.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Schütz
authors.affiliation: Landesuntersuchungsanstalt für das Gesundheits- und Veterinärwesen Sachsen, 04158 Leipzig, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hardt
authors.affiliation: Landesuntersuchungsanstalt für das Gesundheits- und Veterinärwesen Sachsen, 04158 Leipzig, Germany.
authors.forename: Petra
authors.initials: P
authors.lastname: Scheuermann
authors.affiliation: Veterinary Practice Zettlitz, Straße der Jugend 68, 09306 Zettlitz, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Freick
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002417:Cattle; D002418:Cattle Diseases / Q000175:diagnosis / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D004480:Ectromelia / Q000662:veterinary*; D005091:Exons; D020440:Gene Duplication; D005838:Genotype; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D016415:Sequence Alignment; D013577:Syndrome; D013977:Tibia / Q000002:abnormalities*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics*
chemical_list: C416676:ALX4 protein, human; D004268:DNA-Binding Proteins; D014157:Transcription Factors