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. 2010 Aug;21(7-8):398-408.
doi: 10.1007/s00335-010-9276-4. Epub 2010 Aug 5.

COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia

Orly Goldstein  1 , Richard Guyon, Anna Kukekova, Tatyana N Kuznetsova, Susan E Pearce-Kelling, Jennifer Johnson, Gustavo D Aguirre, Gregory M Acland
Affiliations

COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia

Orly Goldstein et al. Mamm Genome. 2010 Aug.

Abstract

Oculoskeletal dysplasia segregates as an autosomal recessive trait in the Labrador retriever and Samoyed canine breeds, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism and severe ocular defects. The disease phenotype resembles human hereditary arthro-ophthalmopathies such as Stickler and Marshall syndromes, although these disorders are usually dominant. Linkage studies mapped drd1 to canine chromosome 24 and drd2 to canine chromosome 15. Positional candidate gene analysis then led to the identification of a 1-base insertional mutation in exon 1 of COL9A3 that cosegregates with drd1 and a 1,267-bp deletion mutation in the 5' end of COL9A2 that cosegregates with drd2. Both mutations affect the COL3 domain of the respective gene. Northern analysis showed that RNA expression of the respective genes was reduced in affected retinas. These models offer potential for studies such as protein-protein interactions between different members of the collagen gene family, regulation and expression of these genes in retina and cartilage, and even opportunities for gene therapy.

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Figures

Figure 1
Figure 1
drd1-(A) and drd2- (B) informative colony pedigrees used for genome wide scan and multimap analysis. Arrows point to probands. Dashed lines indicate intercross breedings, thick lines backcrosses. Black symbols represent OSD affected dogs, half-black symbols indicate carriers (heterozygotes), and white symbols identify homozygous normal dogs. Numbers in parentheses are the number of dogs in each category used in analysis.
Figure 1
Figure 1
drd1-(A) and drd2- (B) informative colony pedigrees used for genome wide scan and multimap analysis. Arrows point to probands. Dashed lines indicate intercross breedings, thick lines backcrosses. Black symbols represent OSD affected dogs, half-black symbols indicate carriers (heterozygotes), and white symbols identify homozygous normal dogs. Numbers in parentheses are the number of dogs in each category used in analysis.
Figure 2
Figure 2
Schematic illustrations of COL9A2 (A) and COL9A3 (B) mRNAs and their corresponding protein domains. Shaded areas in the mRNA correspond to the COL domains; unshaded to NC domains. Gray arrows indicate binding sites of primers used to amplify the cDNA. A. The long black arrow and the asterisk (*) indicate the location of the drd2 COL9A2 mutation (deletion of exon 1) and its putative result (a first methionine in exon 5), respectively. B. The diamond symbol (◇) and pound symbol (#) indicate the location of the drd1 COL9A3 mutation (insertion in exon 1) and its result (premature stop codon in exon 2) respectively.
Figure 3
Figure 3. OSD genetic test results for drd2 (A) and drd1 (B)
A1- A subset of the colony pedigree used for the linkage analysis. A2- PCR product from the drd2 COL9A2 mutant allele on a 1.8% agarose gel. A3- PCR product from the COL9A2 normal allele on a 1.8% agarose gel. A normal dog (dog number 13) yields only the normal allele product, an affected dog (dogs number 2, 7, 8) only the mutant product and carrier dogs (remainder) yield both. B- Chromatograms of normal, drd1-carrier and drd1-affected dogs. Four Guanines are observed in the normal sequence, 5 in affected, and overlapping peaks are observed in sequence from a carrier dog representing the two alleles.
Figure 3
Figure 3. OSD genetic test results for drd2 (A) and drd1 (B)
A1- A subset of the colony pedigree used for the linkage analysis. A2- PCR product from the drd2 COL9A2 mutant allele on a 1.8% agarose gel. A3- PCR product from the COL9A2 normal allele on a 1.8% agarose gel. A normal dog (dog number 13) yields only the normal allele product, an affected dog (dogs number 2, 7, 8) only the mutant product and carrier dogs (remainder) yield both. B- Chromatograms of normal, drd1-carrier and drd1-affected dogs. Four Guanines are observed in the normal sequence, 5 in affected, and overlapping peaks are observed in sequence from a carrier dog representing the two alleles.
Figure 4
Figure 4. RNA expression of COL9A2 (A), COL9A3 (B), and COL9A1(C) in the dog retina
A. COL9A2 is expressed in the retina of a dog not affected with OSD (6.9 weeks old, lane 1) and in drd1-affected retina (7.6 weeks old, lane 2). Two bands are observed of approximately 3.0 Kb and 3.8 Kb long. In drd2-affected retina, COL9A2 is at undetectable levels (12 weeks old, lane 3). B. COL9A3 is expressed in the retina of a dog not affected with OSD (6.9 weeks old, lane 1) and in drd2-affected retina (12 weeks old, lane 3). One band is observed of approximately 3.0 Kb long. In drd1-affected retina, COL9A3 is at undetectable levels (lane 2). C. COL9A1 (short transcript) is expressed in normal retina (10.4 weeks- lane C1 and 4.3 weeks old-lane 2). One band of approximately 3.0 Kb is observed. The long transcript was not detectable in the normal retina (data not shown). Beta actin was used as a loading control.
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References

    1. Acland GM, Aguirre GD. Oculoskeletal dysplasia in samoyed and Labrador retriever dogs: 2 nonallelic disorders akin to Stickler-like syndromes affecting humans. Presented at the 2nd International DOGMAP meeting; Cambridge, Great Britain. 1995.
    1. Acland G, Ray K, Mellersh C, Langston A, Rine J, Ostrander E, Aguirre G. A Novel Retinal Degeneration Locus Identified by Linkage and Comparative Mapping of Canine Early Retinal Degeneration. Genomics. 1999;59(2):134–142. - PubMed
    1. Acland GM, Ray K, Mellersh CS, Gu W, Langston AA, Rine J, Ostrander EA, Aguirre GD. Linkage analysis and comparative mapping of canine progressive rod-cone degeneration (prcd) establishes potential locus homology with retinitis pigmentosa (RP17) in humans. Proc Nat Acad Sc USA. 1998;95(6):3048–53. - PMC - PubMed
    1. Annunen S, Korkko J, Czarny M, Warman ML, Brunner HG, Kaariainen H, Mulliken JB, Tranebjaerg L, Brooks DG, Cox GF, Cruysberg JR, Curtis MA, Davenport SL, Friedrich CA, Kaitila I, Krawczynski MR, Latos-Bielenska A, Mukai S, Olsen BR, Shinno N, Somer M, Vikkula M, Zlotogora J, Prockop DJ, Ala-Kokko L. Splicing mutations of 54-bp exons in the COL11A1 gene cause Marshall syndrome but other mutations cause overlapping Marshall/Stickler phenotypes. Am J Hum Genet. 1999 Oct;65(4):974–83. - PMC - PubMed
    1. Ayme S, Preus M. The Marshall and Stickler syndromes: objective rejection of lumping. J Med Genet. 1984 Feb;21(1):34–8. - PMC - PubMed

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