Dwarfism with joint laxity in Friesian horses is associated with a splice site mutation in B4GALT7

Abstract

BackgroundInbreeding and population bottlenecks in the ancestry of Friesian horses has led to health issues such as dwarfism. The limbs of dwarfs are short and the ribs are protruding inwards at the costochondral junction, while the head and back appear normal. A striking feature of the condition is the flexor tendon laxity that leads to hyperextension of the fetlock joints. The growth plates of dwarfs display disorganized and thickened chondrocyte columns. The aim of this study was to identify the gene defect that causes the recessively inherited trait in Friesian horses to understand the disease process at the molecular level.ResultsWe have localized the genetic cause of the dwarfism phenotype by a genome wide approach to a 3 Mb region on the p-arm of equine chromosome 14. The DNA of two dwarfs and one control Friesian horse was sequenced completely and we identified the missense mutation ECA14:g.4535550C > T that cosegregated with the phenotype in all Friesians analyzed. The mutation leads to the amino acid substitution p.(Arg17Lys) of xylosylprotein beta 1,4-galactosyltransferase 7 encoded by B4GALT7. The protein is one of the enzymes that synthesize the tetrasaccharide linker between protein and glycosaminoglycan moieties of proteoglycans of the extracellular matrix. The mutation not only affects a conserved arginine codon but also the last nucleotide of the first exon of the gene and we show that it impedes splicing of the primary transcript in cultured fibroblasts from a heterozygous horse. As a result, the level of B4GALT7 mRNA in fibroblasts from a dwarf is only 2 % compared to normal levels. Mutations in B4GALT7 in humans are associated with Ehlers-Danlos syndrome progeroid type 1 and Larsen of Reunion Island syndrome. Growth retardation and ligamentous laxity are common manifestations of these syndromes.ConclusionsWe suggest that the identified mutation of equine B4GALT7 leads to the typical dwarfism phenotype in Friesian horses due to deficient splicing of transcripts of the gene. The mutated gene implicates the extracellular matrix in the regular organization of chrondrocyte columns of the growth plate. Conservation of individual amino acids may not be necessary at the protein level but instead may reflect underlying conservation of nucleotide sequence that are required for efficient splicing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-3186-0) contains supplementary material, which is available to authorized users.

Identification of Novel lncRNAs Differentially Expressed in Placentas of Chinese Ningqiang Pony and Yili Horse Breeds

“…As a core transcription factor in embryonic stem cells, ZNF281 (zinc finger protein 281) was found to be related to spontaneous osteochondrogenic differentiation [38]. Other studies showed the strong association of LCORL/NCAPG, HMGA2, PROP1, LASP [39], ZFAT, DIAPH3 [40], ACTN2, ADAMTS17, GH1, ANKRD1 [40], and ACAN [41,42] with miniature size and dwarfism in a variety of pony breeds, including Shetland [41,43], miniature [44], Welsh ponies [45], German warmblood horses [46], American miniature horses, Brazilian ponies [47], and Jeju ponies [48], as well as B4GALT7 [49] and PROP1 [50] in Friesian horses. These genes were not found in this study, which may be due to the expression specificity of lncRNAs in different horse breeds [27] and different omics levels, since TBX3, under strong selection in Chinese ponies, was also identified in this study.…”

Generation of an equine biobank to be used for Functional Annotation of Animal Genomes project

“…Putative causal variants in coding regions have been identified for simple, Mendelian diseases in the horse such as hyperkalemic periodic paralysis (Ptacek et al 1994), hereditary equine regional dermal asthenia (Tryon et al 2007) and dwarfism in Frisian horses (Leegwater et al 2016). However, complex inherited diseases, such as fracture risk (Blott et al 2014), osteochondrosis (van Grevenhof et al 2009; Lykkjen et al 2010; Teyssedre et al 2012; McCoy et al 2016) and recurrent laryngeal neuropathy (Dupuis et al 2011) have failed to be localized to coding regions of the genome despite extensive research.…”

Multiple alleles of ACAN associated with chondrodysplastic dwarfism in Miniature horses

“…Leegwater et al . () described a splice site mutation in beta‐1, 4 galactosyltransferase 7 ( B4GALT7 ), causing disproportionate dwarfism among Fresian horses, that also had a recessive mode of inheritance. In other species, variants in at least 14 genes have been reported to cause conditions characterized as dwarfism (reviewed in Boegheim et al .…”