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Primary lens luxation (PLL)
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Lens luxation (luxatio lentis) is an eye defect connected with dislocation of the lens, which might even result in blinding. PLL (OMIA - Lens luxation, Phene ID 1152, Canis familiaris) was described in dogs more than 75 years ago (Gray et al. 1932).
The lens within the eye is fixed with the fibres of suspensory apparatus and if these fibres break, the lens becomes dislocated from fossa hyaloidea (shallow fossa for the lens in the front side of vitreous body) into the anterior or posterior eye chamber or vitreous body. The lens luxation can also occur in consequence of an injury. The inherited form is caused by defect fixation of the lens zonules or suspensory fibres - loosening of the lens zonules causes dislocation of the lens, which results in glaucoma and entire loss of sight.
The primary lens luxation affects many dog breeds, in particular terriers, puddles, schnauzers, etc., however mutation in connection with the inherited form of PLL has only been found in the following breeds:
Jack Russel Terriere, Miniature bull Terrier, Lancashire Heelers, Tibetan Terrier, Parson Russel Terriere, Patterdale Terrier, Rat Terrier, Sealyham Terrier, Toy Fox Terrier, Volpino Italiano, Welsh Terrier, Chinese Crested, Australian cattle dog, Fox terrier, Yorkshire.
Rarer breeds overrepresented in cases, but for which total PLL affected <6 are Affenpinscher; Brussels Griffon; Chart Polski; Dandie Dinmont terrier; English Toy Spaniel; Japanese Chin; Lowchen; Manchester terrier; Puli; Welsh Springer Spaniel. ( J. Hered et al.2007)
In connection with the inherited PLL, a splice donor site mutation in ADAMTS17-gene was identified, which was proved as casual (Farias et al. 2010). The ADAMTS17-gene is located on the canine chromosome 3 (CFA3). The sequencing of the gene revealed a mutation creating a splice donor site at the 5´ end of intron 10 (Farias et al. 2010). The ADAMST 17-gene (ADAM metallopeptidase with thrombospondin type 1 motif, 17) is one of 19 so far known mammalian genes of the ADAMTS-gene family (a disintegrin and metalloproteinase with thrombospondin motifs), encoding metalloproteases (Cal et al. 2002, Porter et al. 2005). Products of this gene family are necessary for normal growth and development of organs, such as adrenal glands, kidney, uterus and heart. They also participate in pathogenesis of severe human diseases incl. metastasizing carcinomas and arthritis. Mutations or allelic variants of different ADAMTS-genes are associated with a variety of diseases and phenotypes, such as Ehlers-Danlos syndrome of type VIIC, WMS (Weill-Marchesani syndrome), osteoarthritis, osteoporosis, thrombotic thrombocytopenic purpura and abnormal pigment distribution.
A comprehensive study (Faries et al. 2010) has proven the association of the mutation in ADAMTS17-gene with clinical changes in case of inherited form of PLL in three different dog breeds: Miniature Bull Terrier, Jack Russel Terrier and Lancashire Heelers. Within the study, a genotype for splice mutation in canine ADAMTS17 gene was determined in 829 dogs (Farias et al. 2010), out of them 196 dogs with diagnosed PLL and 633 with normal clinical findings.
In the study, 196 dogs were affected with PLL and out of them:
- 161 dogs were homozygous for mutation (genotype A/A)
- 23 dogs were carriers (genotype A/G)
- 12 dogs were without mutation (genotype G/G).
As it is obvious, 35 dogs with clinically positive findings did not have mutated genotype A/A (carriers or dogs without mutation); as the disease may develop even in dogs above 10 years old, it can be assumed that PPL is going to develop in these dogs as they age.
Out of 633 dogs with normal clinical findings, 15 dogs had mutated genotype A/A and all but one were below 6 years of age.
A genotype without mutation G/G was found in 409 dogs, out of them 12 dogs with clinically positive PLL (i.e. 3%). These dogs could have alternative form of PLL (a form with different distribution within the breed, different zonular histopathology; a form caused by different gene mutation described in the study by Faries et. al 2010). The number of dogs with this alternative form will be probably smaller than 3%, as there were preferably included dogs with positive clinical findings for the study purposes.
In the study, the frequency of genotypes in dogs affected by PPL was almost equal in breeds of Jack Russel Terriers (2.5% genotype A/G and 2,1% genotype G/G) and Langshire heelers (9.8% genotype A/G and 8.0% genotype G/G ). In PLL-affected Miniature Bullterriers, the percentage of heterozygous genotype representation (14%) has been five times higher that the percentage of the normal homozygous genotype representation G/G (2.7%) (Farias et al. 2010). This genotype representation shows that also for the carriers of A/G-mutation the risk of development of PPL is higher. The risk depends on the specific breed or genetic background of the individual dogs (Farias et al. 2010).
At present, the occurrence frequencies of genotypes and individual alleles in all breeds affected by PLL are not available for all breeds.
A genetic examination reveals only presence or absence of the donor splice site mutation of ADAMTS17-gene that is nowadays considered to cause PLL. The examination performed neither excludes the possibility of other PLL-form nor reveals the development of the disease in carriers of the mutation.
The general inheritance of PLL is considered autosomal recessive and therefore the disease does not develop in the most carriers of ADAMTS17-mutation during their lives. With regard to the data found, a small percentage of PLL-carriers become ill; the disease develops in 2 to 20% carriers of the mutation (the assumption is rather close to the lower limit). As the cause of disease development is not known, it is recommended that the carriers are monitored during their lives and subject to regular ophthalmological examinations (approx. every 6 to 12 month from 2 years of age). The incidence of carriers in the individual breeds can be high. It is recommended that dogs with genotype N/P (a carrier of the mutation) shall be covered only by a dog with genotype N/D (without mutation).
In dogs, where 2 copies of mutated gene (P/P) were found, it can be expected that the PLL develops in the course of the life. Monitoring by an ophthalmologist is recommended so that the symptoms are revealed as soon as possible.
Farias FH, Johnson GS, Taylor JF, Giuliano E, Katz ML, Sanders DN, Schnabel RD, McKay SD, Khan S, Gharahkhani P, O'Leary CA, Pettitt L, Forman OP, Boursnell M,McLaughlin B, Ahonen S, Lohi H, Hernandez-Merino E, Gould DJ, Sargan DR, Mellersh C.: An ADAMTS17 splice donor site mutation in dogs with primary lens luxation. Invest Ophthalmol Vis Sci. 2010 Sep;51(9):4716-21.
Gould D, Pettitt L, McLaughlin B, Holmes N, Forman O, Thomas A, Ahonen S, Lohi H, O'Leary C, Sargan D, Mellersh C.: ADAMTS17 mutation associated with primary lens luxation is widespread among breeds. Vet Ophthalmol. 2011 Nov;14(6):378-84
Gray H. Some medical and surgical conditions in the dog. Vet Rec.1932;12:1-10.
Morales J, Al-Sharif L, Khalil DS, et al. Homozygous mutations in ADAMTS10 and ADAMTS17 cause lenticular myopia, ectopia lentis, glaucoma, spherophakia, and short stature. Am J Hum Genet. 2009;85:558-568.
Cal S, Obaya AJ, Llamazares M, Garabaya C, Quesada V, Lo´pez-Otín C. Cloning, expression analysis, and structural characterization of seven novel human ADAMTSs, a family of metalloproteinases with disintegrin and thrombospondin-1 domains. Gene. 2002;283: 49-62.
Porter S, Clark IM, Kevorkian L, Edwards DR. The ADAMTS metalloproteinases. Biochem J. 2005;386:15-27.
J. Hered, David R. Sargan, Louise Pettitt, Michael Squire, David J. Gould, Cathryn S. Mellersh:Mapping the Mutation Causing Lens Luxation in Several Terrier Breeds. 2007; 98 (5): 534-538
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