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.
Highlights
Vertebrate limb development is a complex process regulated by two signalling centres, the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) [1, 2]
In humans tibial hemimelia or agenesis has been described in combination with other more apparent defects, e.g. ectrodactyly and femoral duplication in Gollop-Wolfgang complex [42,43,44], multiple exostoses and mental retardation in Langer-Giedion syndrome [45], or partial alopecia, frontonasal dysplasia, and hypogonadism in Potocki-Shaffer syndrome [46]
In GollopWolfgang complex and Langer-Giedion syndrome, deletions on chromosome 8q have been identified, whereas Potocki-Shaffer syndrome is caused by deletion and/or mutations of the Aristaless-like homeobox 4 (ALX4) gene on chromosome 11p11.2 [7, 17]
Summary
Vertebrate limb development is a complex process regulated by two signalling centres, the apical ectodermal ridge (AER) and the zone of polarizing activity (ZPA) [1, 2]. Within these centres, several genes coordinate limb growth along the anteroposterior (AP), dorsoventral and proximodistal axes. Once the limb has formed from the shoulder and/or pelvic girdle to the PLOS ONE | DOI:10.1371/journal.pone.0129208. Once the limb has formed from the shoulder and/or pelvic girdle to the PLOS ONE | DOI:10.1371/journal.pone.0129208 June 15, 2015
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