Dataset Information

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.

SUBMITTER: Brenig B

PROVIDER: S-EPMC4468193 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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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.

Brenig Bertram B Schütz Ekkehard E Hardt Michael M Scheuermann Petra P Freick Markus M

PloS one 20150615 6

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 ...[more]

PMID: 26076463

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Project description:RATIONALE:Tibial hemimelia is known as a rare congenital lower limb deficiency. It has been classified into different types based on Jones classification, and the traditional treatment of tibial hemimelia is amputation. Here we present a variant and unclassified case of tibial hemimelia, which was caused by osteomyelitis. And the lower limb with tibial hemimelia was salvaged by asymmetric limb lengthening. PATIENT CONCERNS:19-year-old girl had the shortened and curved left lower extremity with walking abnormalities. DIAGNOSIS:The patient's deformity was caused by osteomyelitis of tibia occurred when she was 18 month old. The tibial shaft was absent, while the proximal and distal tibia was present but was hypoplastic with radiographic analysis. The fibula was hypertrophied and curved like the capital letter C. The leg length discrepancy (LLD), mostly coming from the left lower leg, was 22 cm. INTERVENTIONS:We were able to salvage the limb successfully by 5 operations, including releasing soft tissue, fusing the proximal tibiofibular joint, fibular osteotomy, femur lengthening, and fibular lengthening. OUTCOMES:The whole treatment time for the patient was 3 years and 2 months, and she was followed up for 5 years afterward. The length of femur lengthening and fibula lengthening during the reconstruction were 7.8 cm and 11 cm, respectively. Most of the deformities were corrected, except that the left lower limb was still 2 cm shorter than the contralateral limb, and the 34 mm of mechanical axis deviation (MAD) of left lower limb remained. The reason why the patient's lower limbs were asymmetric was that the femur and fibular lengthening were performed within the affected limb only. Overall, the patient was very satisfied with her asymmetric limbs and its function after surgeries. LESSONS:The LLD in this case mainly came from tibial hemimelia. However, the fibula was unable to be lengthened to 22 cm during the lower leg distraction process because of blood flow disturbance. We could only lengthen the femur to salvage the limb in this situation. Even though the patient still had a few residual deformities and a pair of asymmetric lower limbs, she was satisfied with the function and appearance of the reconstructed limb. Therefore, the lower limb with tibial hemimelia can be salvaged by asymmetric limb lengthening in special cases.

Dataset Information

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.

Publications

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.

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