A Contracted DNA Repeat in LHX3 Intron 5 Is Associated with Aberrant Splicing and Pituitary Dwarfism in German Shepherd Dogs

Voorbij, Annemarie M.W.Y.; Steenbeek, Frank G. van; Vos-Loohuis, Manon; Martens, Ellen; Hanson, Jeanette; Oost, B.A. van; Kooistra, Hans S.; Leegwater, P.A.J.

doi:10.1371/journal.pone.0027940

Cited by 24 publications

(47 citation statements)

References 48 publications

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“…As discussed earlier, pituitary dwarfism in the German Shepherd dog (and related breeds such as the Karelian Bear dog, Saarloos Wolfhound, and Czechoslovakian Wolfdog) is due to a mutation in the LHX3 gene (Voorbij et al, 2011). As discussed earlier, pituitary dwarfism in the German Shepherd dog (and related breeds such as the Karelian Bear dog, Saarloos Wolfhound, and Czechoslovakian Wolfdog) is due to a mutation in the LHX3 gene (Voorbij et al, 2011).…”

Section: Endocrinological Evaluation and Diagnosismentioning

confidence: 86%

“…2-2 for the differentiation of pituitary cell lineages and the main important transcription factors involved. More recently, the search was successful, and the genetic defect could be located in the LHX3 gene (Voorbij et al, 2011). It was, therefore, reasonable to explore potential defects in those two genes also in the German Shepherd.…”

Section: Non-endocrine Causes Of Growth Failurementioning

confidence: 99%

“…In the German Shepherd dog the genetic defect has recently been identified (Voorbij et al, 2011), and it seems that the defect is identical in the Karelian Bear dog and the Wolfhound breeds in which the German Shepherd has been used for breeding. In the German Shepherd dog the genetic defect has recently been identified (Voorbij et al, 2011), and it seems that the defect is identical in the Karelian Bear dog and the Wolfhound breeds in which the German Shepherd has been used for breeding.…”

Section: Signalmentmentioning

confidence: 99%

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Disorders of Growth Hormone

Reusch¹

2015

Canine and Feline Endocrinology

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Section: Endocrinological Evaluation and Diagnosismentioning

confidence: 86%

Section: Non-endocrine Causes Of Growth Failurementioning

confidence: 99%

Section: Signalmentmentioning

confidence: 99%

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Disorders of Growth Hormone

Reusch¹

2015

Canine and Feline Endocrinology

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“…Considering all our results, we conclude that the conservation of the exon 1 terminal sequence in vertebrates reflects a restriction on a splicing requirement rather than on a functional requirement of the encoded amino acid. Characterization of naturally occurring mutations that are uncovered because of an association with disease can render important insights in splicing requirements [12]. …”

Section: Discussionmentioning

confidence: 99%

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

et al. 2016

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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.

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“…Recently, we have reported that molecular defects of the LHX3 gene are associated with CPHD . LHX3, a member of the LIM homeodomain protein family of DNA‐binding transcription factors, is an essential regulator of pituitary development .…”

mentioning

confidence: 99%

Pituitary Dwarfism in Saarloos and Czechoslovakian Wolfdogs is Associated with a Mutation in LHX3

Voorbij

Leegwater

Kooistra

2014

Veterinary Internal Medicne

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BackgroundPituitary dwarfism in German Shepherd Dogs is associated with autosomal recessive inheritance and a mutation in LHX3, resulting in combined pituitary hormone deficiency. Congenital dwarfism also is encountered in breeds related to German Shepherd Dogs, such as Saarloos and Czechoslovakian wolfdogs.ObjectivesTo investigate whether Saarloos and Czechoslovakian wolfdog dwarfs have the same LHX3 mutation as do Germans Shepherd Dog dwarfs. A specific aim was to determine the carrier frequency among Saarloos and Czechoslovakian wolfdogs used for breeding.AnimalsTwo client‐owned Saarloos wolfdogs and 4 client‐owned Czechoslovakian wolfdogs with pituitary dwarfism, 239 clinically healthy client‐owned Saarloos wolfdogs, and 200 client‐owned clinically healthy Czechoslovakian wolfdogs.MethodsGenomic DNA was amplified using polymerase chain reaction (PCR). In the Saarloos and Czechoslovakian wolfdog dwarfs, PCR products were analyzed by sequencing. DNA fragment length analysis was performed on the samples from the clinically healthy dogs.ResultsSaarloos and Czechoslovakian wolfdog dwarfs have the same 7 bp deletion in intron 5 of LHX3 as do German Shepherd Dog dwarfs. The frequency of carriers of this mutation among clinically healthy Saarloos and Czechoslovakian wolfdogs used for breeding was 31% and 21%, respectively.Conclusions and Clinical ImportanceAn LHX3 mutation is associated with pituitary dwarfism in Saarloos and Czechoslovakian wolfdogs. The rather high frequency of carriers of the mutated gene in the 2 breeds emphasizes the need for screening before breeding. If all breeding animals were genetically tested for the presence of the LHX3 mutation and a correct breeding policy would be implemented, this disease could be eradicated completely.

show abstract

A Contracted DNA Repeat in LHX3 Intron 5 Is Associated with Aberrant Splicing and Pituitary Dwarfism in German Shepherd Dogs

Cited by 24 publications

References 48 publications

Disorders of Growth Hormone

Disorders of Growth Hormone

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

Pituitary Dwarfism in Saarloos and Czechoslovakian Wolfdogs is Associated with a Mutation in LHX3

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