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Sabrina Stritzel (2008)

Familial and breed specific hereditary diseases in dogs

The objective of this study was to examine canine diseases occurring basically in certain breeds or families and so suggesting a genetic background. The role of a couple of genes in the development of the following diseases appearing in definite dog populations was examined in this work:

Canine pituitary-dependent hyperadrenocorticism

The cause of hyperadrenocorticism or Cushing’s disease is an excessive production of cortisol by the adrenal cortex. In case of a secondary or pituitary-dependent hyperadrenocorticism the origin is a pituitary tumor secreting ACTH and so stimulating the adrenal cortex to permanent secretion of cortisol. Especially in smaller dog breeds a frequent occurrence of this disease is recognized. In this work a breed predisposition was confirmed for Dachshunds, Poodles and several Terrier breeds by comparison of different studies describing a breed distribution between affected dogs. In a family of wire-haired Dachshunds seventeen partly closely related animals were affected. These diseased dogs were more closely related than the comparison population. These findings suggest a hereditary disease. Familial Cushing’s disease has only been described in Yorkshire and Dandie Dinmont Terriers yet. Because these three breeds are connected in their breeding history, a common genetic background can be assumed. An expression analysis of MDR1 (multi drug resistance 1) was performed in the liver of one of the affected Dachshunds. The performed

∆∆CT-analysis revealed an obvious increased relative expression of MDR1.

Assumedly this was caused by an up-regulation of MDR1 expression due to the enduring excess of cortisol, which is transported by the MDR1 p-glycoprotein.

Sequence analysis of the coding regions of MDR1 of this dog did not reveal any polymorphism in comparison to the reference sequence of the Boxer, so MDR1 is not supposed be causative for the development of canine pituitary-dependent hyperadrenocorticism.

Ophthalmologic defects in double merles

In two predominantly white Old German sheepdogs and an Old German sheepdog – Australian shepherd mix multiple ocular defects, including multiple, atypical colobomata, dyscoria, persistant pupillary membrane, retinal detachment and microphthalmia, were diagnosed. All three dogs were homozygous for a SINE (short interspersed nuclear element)-insertion in SILV (silver) causing the merle coat pattern. Those dogs often exhibit several anomalies of the eyes and deafness of the inner ear. Because dogs homozygous for this SINE with white coat color, but without any associated defects are also described, it is not clear whereby these anomalies are caused. In merle families a haplotype of SLIV flanking markers segregating with the merle genotype was detected. Nevertheless, no polymorphisms except for the SINE could be revealed in SILV in the three affected dogs. Moreover there was no difference in the length of a poly-A-region included in the SINE between dogs homozygous and heterozygous for the merle mutation. No transcription of the mutated allele of SILV was detected in heterozygous dogs. However, a significant association of flanking and intragenic markers for MITF (microphthalmia-associated transcription factor), which regulates SILV expression during embryogenesis, was identified. These results suggest that SILV is causative for the merle coat pattern, but the ocular defects might be due to additional mutations in or close to MITF.

Congenital sensorineural deafness in Dalmatian dogs

This form of deafness occurs in many dog breeds, especially in white dogs. The highest incidence is recognized in Dalmatian dogs. In this breed, a relationship to pigmentation is described, too. Dalmatians with blue eyes are more often affected, whereas dogs with congenital pigmented patches are less often deaf. Therefore, two genes involved in pigmentation and causing deafness in other dog breeds, human or mice were examined. For this purpose, hearing and deaf Dalmatians with blue and brown eyes were chosen. SILV (silver) causes the merle pattern, which is characterized by diluted coat color and often blue eyes in many dog breeds. Dogs homozygous for the merle factor can be affected by deafness of the inner ear, too.

Neither the merle causing SINE nor any other polymorphism in the coding sequences

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of SILV was identified in the examined Dalmatian dogs. So this gene can be excluded to be responsible for congenital sensorineural deafness in Dalmatian dogs.

The microphthalmia-associated transcription factor (MITF) causes congenital deafness associated with lack of pigmentation of the iris, hair and skin in human and mice. Moreover, it is associated with the white coat color in many dog breeds, including Dalmatians. White dogs often are affected by deafness, too. For the Dalmatians, flanking and intragenic markers for MITF were genotyped. For some of these markers a significant association to deafness and blue iris color was identified.

Therefore, MITF could be involved in congenital sensorineural deafness in Dalmatian dogs.

Lundehund gastroenteropathy

Norwegian lundehunds often are affected by a gastroenteropathy-syndrome characterized by diarrhoea and vomitus and caused by gastritis, protein-losing enteropathy, intestinal lymphangiectasia and inflammatory bowel disease. The described prevalence in this rather small population is about 40-50 %. A joint pedigree was established for all examined lundehunds in this work. So a genetic background can be assumed for this disease. One finding in affected Lundehunds is a deficiency of cobalamin. Malabsorptions of cobalamin in dogs (Giant Schnauzer and Australian Shepherd) can be caused by mutations in the amnionless (AMN) gene coding for a part of the cobalamin receptor. Therefore, AMN could also play a role in the disease of these lundehunds. The described mutations were not identified in the examined dogs. Moreover, a linkage and association study with AMN flanking microsatellite and SNP markers did not reveal any significance, and the coding sequences of AMN showed no polymorphisms. Therefore, we conclude that AMN is not involved in the Lundehund-gastroenteropathy.

Kapitel 11

Anhang

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