title: A frameshift mutation in GON4L is associated with proportionate dwarfism in Fleckvieh cattle.
abstract: BACKGROUND
  Low birth weight and postnatal growth restriction are the most evident symptoms of dwarfism. Accompanying skeletal aberrations may compromise the general condition and locomotion of affected individuals. Several paternal half-sibs with a low birth weight and a small size were born in 2013 in the Fleckvieh cattle population.
  
  
  RESULTS
  Affected calves were strikingly underweight at birth in spite of a normal gestation length and had craniofacial abnormalities such as elongated narrow heads and brachygnathia inferior. In spite of a normal general condition, their growth remained restricted during rearing. We genotyped 27 affected and 10,454 unaffected animals at 44,672 single nucleotide polymorphisms and performed association tests followed by homozygosity mapping, which allowed us to map the locus responsible for growth failure to a 1.85-Mb segment on bovine chromosome 3. Analysis of whole-genome re-sequencing data from one affected and 289 unaffected animals revealed a 1-bp deletion (g.15079217delC, rs723240647) in the coding region of the GON4L gene that segregated with the dwarfism-associated haplotype. We showed that the deletion induces intron retention and premature termination of translation, which can lead to a severely truncated protein that lacks domains that are likely essential to normal protein function. The widespread use of an undetected carrier bull for artificial insemination has resulted in a tenfold increase in the frequency of the deleterious allele in the female population.
  
  
  CONCLUSIONS
  A frameshift mutation in GON4L is associated with autosomal recessive proportionate dwarfism in Fleckvieh cattle. The mutation has segregated in the population for more than 50 years without being recognized as a genetic disorder. However, the widespread use of an undetected carrier bull for artificial insemination caused a sudden accumulation of homozygous calves with dwarfism. Our findings provide the basis for genome-based mating strategies to avoid the inadvertent mating of carrier animals and thereby prevent the birth of homozygous calves with impaired growth.
authors.affiliation: ZuchtData EDV-Dienstleistungen GmbH, 1200, Vienna, Austria.
authors.forename: Hermann
authors.initials: H
authors.lastname: Schwarzenbacher
authors.affiliation: Chair of Animal Breeding, Technical University of Munich, 85354, Freising, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Wurmser
authors.affiliation: Chair of Animal Biotechnology, Technical University of Munich, 85354, Freising, Germany.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Flisikowski
authors.affiliation: Clinic for Ruminants with Ambulatory and Herd Health Services at the Centre for Clinical Veterinary Medicine, Ludwigs-Maximilians-Universitaet Muenchen, 85764, Oberschleissheim, Germany.
authors.forename: Lubica
authors.initials: L
authors.lastname: Misurova
authors.affiliation: Chair of Animal Breeding, Technical University of Munich, 85354, Freising, Germany.|Bayern Genetik GmbH, 85586, Poing, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Jung
authors.affiliation: Institute of Veterinary Pathology at the Centre for Clinical Veterinary Medicine, Ludwigs-Maximilians-Universitaet Muenchen, 80539, Munich, Germany.|Institute for Infectious Diseases and Zoonoses, Ludwigs-Maximilians-Universitaet Muenchen, 80539, Munich, Germany.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Langenmayer
authors.affiliation: Chair of Animal Biotechnology, Technical University of Munich, 85354, Freising, Germany.
authors.forename: Angelika
authors.initials: A
authors.lastname: Schnieke
authors.affiliation: Clinic for Ruminants with Ambulatory and Herd Health Services at the Centre for Clinical Veterinary Medicine, Ludwigs-Maximilians-Universitaet Muenchen, 85764, Oberschleissheim, Germany.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Knubben-Schweizer
authors.affiliation: Chair of Animal Breeding, Technical University of Munich, 85354, Freising, Germany.
authors.forename: Ruedi
authors.initials: R
authors.lastname: Fries
authors.affiliation: Chair of Animal Breeding, Technical University of Munich, 85354, Freising, Germany. hubert.pausch@tierzucht.tum.de.
authors.forename: Hubert
authors.initials: H
authors.lastname: Pausch
mesh_terms: D000483:Alleles; D000818:Animals; D002417:Cattle; D002418:Cattle Diseases / Q000235:genetics*; D004392:Dwarfism / Q000235:genetics / Q000662:veterinary*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics*; D005808:Genes, Recessive; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014157:Transcription Factors