A KCNJ10 mutation previously identified in the Russell group of terriers also occurs in Smooth-Haired Fox Terriers with hereditary ataxia and in related breeds

Background

Hereditary ataxias with similar phenotypes were reported in the Smooth-Haired Fox Terrier, the Jack Russell Terrier and the Parson Russell Terrier. However, segregation analyses showed differing inheritance modes in these breeds. Recently, molecular genetic studies on the Russell group of terriers found independent mutations in KCNJ10 and CAPN1, each associated with a specific clinical subtype of inherited ataxia. The aim of this study was to clarify whether or not Smooth-Haired Fox Terriers with hereditary ataxia and dogs of other related breeds harbor either of the same mutations. A sub goal was to update the results of KCNJ10 genotyping in Russell group terriers.

Findings

Three Smooth-Haired Fox Terriers with hereditary ataxia and two Toy Fox Terriers with a similar phenotype were all homozygous for the KCNJ10 mutation. The same mutation was also found in a heterozygous state in clinically unaffected Tenterfield Terriers (n = 5) and, in agreement with previous studies, in Jack Russell Terriers, Parson Russell Terriers, and Russell Terriers.

Conclusions

A KCNJ10 mutation, previously associated with an autosomal recessive spinocerebellar ataxia in Jack Russell Terriers, Parson Russell Terriers, and Russell Terriers segregates in at least three more breeds descended from British hunting terriers. Ataxic members of two of these breeds, the Smooth-Haired Fox Terrier and the Toy Fox Terrier, were homozygous for the mutation, strengthening the likelihood that this genetic defect is indeed the causative mutation for the disease known as “hereditary ataxia” in Fox Terriers and “spinocerebellar ataxia with myokymia, seizures or both” in the Russell group of terriers.     

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

Background

Pituitary 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.

Objectives

To 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.

Animals

Two 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.

Methods

Genomic 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.

Results

Saarloos 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 Importance

An 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.     

Congenital hypothyroidism with goiter in toy fox terriers

Congenital hypothyroidism with goiter was observed to segregate as a simple autosomal recessive trait in Toy Fox Terriers (TFTs). Neonatal affected pups exhibited inactivity, abnormal hair coat, stenotic ear canals, and delayed eye opening. Palpable ventrolateral cervical swellings were evident by 1 week of age. Serum thyroid hormone and thyroid-stimulating hormone concentrations were low and high, respectively. Histologic examination of the cervical masses disclosed cuboidal to columnar follicular epithelial cell hyperplasia with widely varying follicular size, shape, and amount of colloid. Oral thyroid hormone replacement therapy restored near-normal growth and development. At 8 weeks of age, radioiodine uptake and perchlorate discharge testing indicated an iodine organification defect. Biochemical analysis of thyroid tissue from affected dogs demonstrated enzymatic iodine oxidation deficiency and lack of sodium dodecyl sulfate-resistant thyroglobulin dimers, suggesting thyroid peroxidase deficiency. A nonsense mutation in the thyroid peroxidase gene of affected dogs was discovered and demonstrated to segregate with the disease. A DNA-based carrier test was developed and currently is used by TFT breeders to prevent this disorder.     

CNS hypomyelination in Rat Terrier dogs with congenital goiter and a mutation in the thyroid peroxidase gene

Arrested physical development and neurologic abnormalities were identified in 3 of 5 Rat Terrier puppies at 9 weeks of age. Bilaterally firm symmetrical masses were palpated in the region of the thyroid glands. Low serum total (T4) and free thyroxine (FT4, by equilibrium dialysis) and markedly elevated thyroid stimulating hormone (TSH) concentrations supported the diagnosis of hypothyroidism. At necropsy, the thyroid gland was grossly enlarged and histologically exhibited severe, diffuse hyperplasia of the follicular epithelium. Gross examination of the central nervous system revealed a myelin deficiency, most evident in the corpus callosum. Regional distribution of hypomyelination was confirmed histologically, affecting the corpus callosum and, to a lesser degree, the corona radiata, the longitudinal fibers of the pons, the pyramids, and the lateral funiculi of the spinal cord. Myelin reduction was paralleled by axon reduction, suggesting that hypomyelination was a consequence of reduced axonal formation. A homozygous nonsense mutation in the thyroid peroxidase gene was identified in the affected puppies. The dam and a clinically normal litter mate were heterozygous for this mutation, confirming simple autosomal recessive inheritance of the disease trait. The same mutation, causing congenital hypothyroidism with a goiter was previously described in the Toy Fox Terrier breed. Given the ongoing practice of introducing the Toy Fox Terrier genetic background into some Rat Terrier breeding programs to obtain a smaller stature and the apparent relative incidence of the disorder in the 2 breeds, it is likely that this mutation crossed into the Rat Terrier breed from Toy Fox Terriers fairly recently.     

Combined pituitary hormone deficiency in german shepherd dogs with dwarfism

In German shepherd dogs pituitary dwarfism is known as an autosomal recessive inherited abnormality. To investigate whether the function of cells other than the somatotropes may also be impaired in this disease, the secretory capacity of the pituitary anterior lobe (AL) cells was studied by a combined pituitary AL stimulation test with four releasing hormones (4RH test) in four male and four female German shepherd dwarfs. In addition, the morphology of the pituitary was investigated by computed tomography. The physical features of the eight German shepherd dwarfs were primarily characterized by growth retardation and stagnant development of the hair coat. The results of the 4RH test confirmed the presence of hyposomatotropism. The basal plasma TSH and prolactin concentrations were also low and did not change upon stimulation. Basal plasma concentrations of LH were relatively low and responded only slightly to suprapituitary stimulation. With respect to the plasma FSH levels there was a clear gender difference. In the males plasma FSH concentrations remained below the detection limit throughout the 4RH test, whereas in the females the basal plasma FSH levels were slightly lower and there was only a small increase following suprapituitary stimulation, compared with the values in age-matched controls. In contrast, basal and stimulated plasma ACTH concentrations did not differ between the dwarfs and the controls. Computed tomography of the pituitary fossa revealed a normal sized pituitary with cysts in five dogs, an enlarged pituitary with cysts in two dogs, and a small pituitary gland without cysts in the remaining dog. The results of this study demonstrate that German shepherd dwarfs have a combined deficiency of GH, TSH, and prolactin together with impaired release of gonadotropins, whereas ACTH secretion is preserved. The combined pituitary hormone deficiency is associated with cyst formation and pituitary hypoplasia.     

Inherited congenital extrahepatic portosystemic shunts in Cairn terriers

The pathogenesis of congenital portosystemic shunt (CPSS) in dogs still is incompletely understood. In Irish Wolfhounds and Yorkshire Terriers, CPSS is reported to be hereditary. The aim of this study was to investigate a possible genetic basis and the mode of inheritance of CPSS in Cairn Terriers. Between July 1990 and July 2001, 6-week-old pups of the Dutch Cairn Terrier population were screened by measuring venous ammonia concentrations and in the presence of hyperammonemia by ultrasonography, autopsy, portal vein angiography, or exploratory celiotomy. The same successfully operated female was used 3 times in test matings with an unrelated affected male, her unaffected sire, and an affected offspring. The prevalence of CPSS in the general Cairn Terrier population, the direct progeny of frequently used males, and the offspring of the test matings were tested for significant differences. In total, 6,367 Cairn Terriers were screened; 32 males and 26 females had CPSS. In 3 large family groups, significantly higher prevalences were found compared with the general population (P < .0001, P < .0001, and P < .044). The prevalence of CPSS in the offspring of the test matings was significantly higher (P < .002) than in the general population. No sex predisposition occurred among the affected dogs. The higher prevalence of CPSS in the test matings and the 3 family groups compared with the general population indicates that CPSS in Cairn Terriers is a genetic disease. The inheritance is autosomal and most likely polygenic or monogenic with variable expression.     

Hereditary dwarfism in pigs

In a swine production herd dwarfs with extremely short limbs were observed in 3 litters sired by the same boar. Clinical, radiographical, and pathologic-anatomical examinations, showed the affected individuals to be chondrodysplastic dwarfs. Such dwarfism has not been reported previously in pigs. An inbreeding experiment conducted with a dwarf gilt and related boars indicated that the dwarfism was hereditary with a simple autosomal recessive inheritance.     

Assessment of retinal function and characterization of lysosomal storage body accumulation in the retinas and brains of Tibetan Terriers with ceroid-lipofuscinosis

OBJECTIVE: To characterize lysosomal storage body accumulation in the retina and brain of Tibetan Terriers with ceroid-lipofuscinosis and determine whether the disease in these dogs is accompanied by impaired retinal function and retinal degeneration. ANIMALS: Three 7- to 10-year-old Tibetan Terriers with ceroid-lipofuscinosis and 1 healthy 5-year-old Tibetan Terrier. PROCEDURE: Owners completed a questionnaire to identify behavioral and physical signs indicative of ceroid-lipofuscinosis. Neurologic, behavioral, and ophthalmologic evaluations, including full-field electroretinograms, were performed on each dog. Fluorescence, light, and electron microscopy were performed on specimens of retina, cerebral cortex, and cerebellum of all dogs postmortem. RESULTS: Behavioral assessments of the affected dogs revealed moderate visual impairment in low-light conditions but good vision in bright light. On funduscopic evaluation of these dogs, abnormalities detected ranged from none to signs of moderately advanced retinal degeneration. Compared with findings in the control dog, electroretinography revealed depressed rod cell function with some impairment of cone cell function in the affected dogs. Morphologically, disease-specific storage bodies were detected in retinal Müller cells and neurons, particularly in ganglion cells, and in cells of the cerebral cortex and cerebellum in affected dogs. Substantial photoreceptor cell loss and disruption of photoreceptor outer segment morphology appeared to develop late in the disease. IMPLICATIONS FOR HUMAN MEDICINE: The similarities between ceroid-lipofuscinosis in Tibetan Terriers and some forms of ceroid-lipofuscinosis in humans suggest that the canine disease may have a genetic and biochemical basis similar to that of one of the ceroid-lipofuscinosis disorders in humans.     

Evaluation of haplotypes associated with copper toxicosis in Bedlington Terriers in Australia

OBJECTIVE: To evaluate the haplotype distribution associated with the copper toxicosis gene and the segregation of the mutated allele in a Bedlington Terrier population in Australia. ANIMALS: 131 Bedlington Terriers. PROCEDURE: Samples of DNA and RNA were obtained from each dog. Genetic status of each dog was evaluated by use of the DNA markers C04107; single nucleotide polymorphism (SNP), which was adjacent to exon 2 of Murr1; and a deletion marker for exon 2. A subgroup of the study population was evaluated by use of biochemical and histologic techniques to elucidate the correlation between genotype and phenotype. RESULTS: We identified a recombination between the C04107 marker and Murr1 and a variation in a nucleotide in the splice site of exon 2 in our Bedlington Terrier cohort. Furthermore, we identified a novel haplotype associated with copper toxicosis in this cohort. CONCLUSIONS AND CLINICAL RELEVANCE: Our findings indicate that the deletion of exon 2 was not the sole cause of copper toxicosis, although only exon 2 deletion of Murr1 has been responsible for copper toxicosis in Bedlington Terriers. Although we failed to find a novel mutation in our cohort, we identified an affected dog family with an intact exon 2. Furthermore, we found that an SNP in the 5' splicing site of exon 2 may or may not be associated with a novel mutation of the Murr1 gene or other genes. Loss of linkage between the C04107 marker and the Murr1 gene was also identified in a certain family of dogs.     

Use of proligestone in the management of three German shepherd dogs with pituitary dwarfism

Three German shepherd dogs were diagnosed with pituitary dwarfism and subsequently treated with proligestone. Treatment resulted in development of an adult hair coat, increased bodyweight and elevated insulin-like growth factor-1 concentration. Two dogs received thyroid supplementation during proligestone therapy. Adverse effects (cystic endometrial hyperplasia and acromegaly) were reported in two cases. No side effects were reported in the remaining case. This is the first report of the use of proligestone in the management of pituitary dwarfism.     

Black hair follicular dysplasia, an autosomal recessive condition in dogs.

Using histology, a coat color abnormality and the subsequent hair loss were diagnosed as black hair follicular dysplasia. A pedigree analysis of an affected litter and literature review suggests that this is inherited as an autosomal recessive trait. The melanocyte stimulating hormone receptor gene is ruled out by using linkage analysis.     

Hypochondroplastic dwarfism in the Irish setter

Two test matings in the Irish setter were performed, and genetic, clinical, morphometric, radiographic, bone histological and plasma and urine biochemical features of dwarfism were studied. All offspring were phenotypically normal at birth and weaning, but at the age of 2–5 to 4 months the longitudinal growth of the spine and leg bones was retarded in the dwarfs compared with the normal littermates. Most dwarfs performed well, even in the field. Radiographic and histological evaluations revealed a hypochondroplasia. A morphometric diagnostic method for Irish setter dwarfism was developed. A single autosomal recessive mode of inheritance was verified.     

Pituitary dwarfism in German Shepherd Dogs: a genetic analysis of some Australian data

Eight pituitary dwarfs have been born recently in six different litters from registered German Shepherd parents in the Sydney region of New South Wales, Australia. A genetic analysis has been carried out to determine whether there is any hereditary basis to the syndrome.
In agreement with recent Danish findings, the Australian data indicate that pituitary dwarfism is inherited as an autosomal recessive condition, with the possibility that some recessive homozygotes die before or soon after birth. Thus the observed proportion of dwarfs in a litter from heterozygous parents is often less than 25%.     

Topical flea and tick pesticides and the risk of transitional cell carcinoma of the urinary bladder in Scottish Terriers

OBJECTIVE: To determine whether use of topical flea and tick products increases the risk of transitional cell carcinoma (TCC) of the urinary bladder in Scottish Terriers. DESIGN: Case-control study. ANIMALS: 87 adult Scottish Terriers with TCC (cases) and 83 adult Scottish Terriers with other health-related conditions (controls). PROCEDURE: Owners of study dogs were recruited through private veterinary practices and the Scottish Terrier Club of America. History of exposure to flea and tick products 1 year prior to diagnosis of TCC for case dogs and during a comparable period for control dogs was obtained through a questionnaire. Risk of TCC associated with exposure to flea and tick products was determined by means of univariate and multiple logistic regression analysis. RESULTS: After adjustment for host factors, Scottish Terriers treated with topical spot-on flea and tick products containing fipronil or imidacloprid did not have an increased risk of TCC, compared with Scottish Terriers that had never been exposed to any flea and tick products. The risk of TCC associated with use of older topical flea and tick products such as shampoos, dips, powders, sprays, and collars could not be evaluated because of the low number of owners in the study population that had used such products. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggest that use of topical spot-on flea and tick products does not increase the risk of TCC in Scottish Terriers.     

Assessment of plasma carnitine concentrations in relation to ceroid lipofuscinosis in Tibetan Terriers

OBJECTIVE: To determine whether the late onset form of inherited ceroid lipofuscinosis (CL) in Tibetan Terriers is accompanied by low plasma carnitine concentrations prior to the appearance of clinical signs. ANIMALS: 129 healthy Tibetan Terriers, 12 Tibetan Terriers with CL, and 95 healthy purebred dogs of other breeds. PROCEDURE: After withholding food, blood samples were collected from all dogs into tubes containing EDTA. Blood samples were analyzed for plasma-free carnitine and acyl-carnitines concentrations. RESULTS: Neither the mean plasma total carnitine concentration nor the mean fraction of carnitine in the free form differed significantly between Tibetan Terriers with CL and healthy Tibetan Terriers. Among Tibetan Terriers and the general dog population, plasma carnitine concentration increased with age. Castrated males had an overall increase in plasma carnitine concentrations and variability, compared with sexually intact males. By comparison, plasma carnitine concentrations were not significantly different between spayed and sexually intact females. The mean plasma carnitine concentration in the Tibetan Terriers was approximately 22% higher than in the general population of healthy dogs of other breeds. CONCLUSIONS AND CLINICAL RELEVANCE: Contrary to what is seen in early onset CL in English Setters and in humans with some forms of CL, plasma carnitine concentrations are not decreased in the late-onset disorder in Tibetan Terriers. Our large-scale study establishes reference range values for plasma carnitine concentrations in dogs as functions of age and sex that will be useful in evaluating potential carnitine deficiencies in other disorders in dogs.     

Cataract in the West Highland White Terrier

Cataracts were found in 49 of 97 interrelated West Highland White Terriers. Thirty-four dogs exhibited a ‘y’ suture cataract, mainly affecting the tips of the posterior ‘y’ suture line, while 12 dogs had complete cataracts. An autosomal recessive inheritance is surmised.     

Atlanto‐Axial Malformation and Instability in Dogs with Pituitary Dwarfism due to an LHX3 Mutation

Background

Canine pituitary dwarfism or combined pituitary hormone deficiency (CPHD) in shepherd dogs is associated with an LHX3 mutation and can lead to a wide range of clinical manifestations. Some dogs with CPHD have neurological signs that are localized to the cervical spine. In human CPHD, caused by an LHX3 mutation, anatomical abnormalities in the atlanto‐axial (C1‐C2) joint have been described.

Objectives

To evaluate the presence of atlanto‐axial malformations in dogs with pituitary dwarfism associated with an LHX3 mutation and to investigate the degree of similarity between the atlanto‐axial anomalies found in canine and human CPHD patients with an LHX3 mutation.

Animals

Three client‐owned Czechoslovakian wolfdogs and 1 client‐owned German shepherd dog, previously diagnosed with pituitary dwarfism caused by an LHX3 mutation, with neurological signs indicating a cervical spinal disorder.

Methods

Radiography, computed tomography, and magnetic resonance imaging of the cranial neck and skull, necropsy, and histology.

Results

Diagnostic imaging identified abnormal positioning of the dens axis and incomplete ossification of the suture lines between the ossification centers of the atlas with concurrent atlanto‐axial instability and dynamic compression of the spinal cord by the dens axis. The malformations and aberrant motion at C1–C2 were confirmed at necropsy and histology.

Conclusions and Clinical Importance

The atlanto‐axial abnormalities of the dwarf dogs resemble those encountered in human CPHD patients with an LHX3 mutation. These findings suggest an association between the LHX3 mutation in dogs with CPHD and atlanto‐axial malformations. Consequently, pituitary dwarfs should be monitored closely for neurological signs.     

Primary lens luxation in the Chinese Shar Pei: clinical and hereditary characteristics

A pedigree analysis of a family of 15 related Chinese Shar Peis was conducted. This pedigree analysis, including affected and nonaffected dams, sires and offspring, was compiled to document and characterize the occurrence, common clinical signs, and age of onset of primary lens luxation while suggesting a possible mode of inheritance in this breed. Of the five offspring from the mating of an affected dam to two unrelated affected males, 100% of offspring were affected with bilateral primary lens luxations. Of the four viable offspring from the mating of the same affected dam to an unrelated, unaffected male, two dogs (50%) were affected. The average age of onset of affected animals (seven) in this first generation was 4.9 years (range 3–6 years). The six dogs in the second generation of the same pedigree line were 2-years-old at examination with none of these animals affected at the time of this study. The most common presenting complaints were a unilateral change in ocular appearance (5 of 7 dogs) and subjective vision impairment (4 of 7 dogs). The most common clinical sign upon ophthalmic examination was iridodonesis (unilateral 4 of 7 dogs; bilateral 3 of 7 dogs) and the presence of an aphakic crescent (3 of 7 dogs). Gonioscopy and tonometry of severely affected eyes revealed a narrow or closed iridocorneal angle and ocular hypertension. This study suggests that primary lens luxation does occur in the Chinese Shar Pei, resembling the clinical condition (age of onset, clinical signs) previously described in the terrier breeds, the Border Collie, and the Tibetan Terrier. Application of the phenotypic findings in this study to a Mendelian genetic model of inheritance suggests that primary lens luxation in the Chinese Shar Pei is inherited as a simple autosomal recessive trait.     

Dwarfism in Hereford cattle: a genetic morphological and biochemical study

A study of 40 Hereford cattle dwarfs in New Zealand confirmed that dwarfism in this country was morphologically the same as that described in North American Herefords and that its mode of inheritance was as an autosomal recessive trait. The histological architecture of growth plates was essentially normal but palisading columns were shorter and more irregular than in controls. A small proportion of cbondrocytes in dwarf cartilage showed increased areas of cytoplasmic metachromasia, which probably coincided with increased cystic dilations of endoplasmic reticulum containing granular material as noted by electronmicroscopy. The above growth-plate abnormalities were neither prominent nor consistent enough to be of diagnostic significance; nor do they currently help understanding of the underlying pathogenic mechanism of dwarfing. Histological and mucopolysaccharide excretion studies unequivocally demonstrated that this disease is not a mucopolysaccharidosis as had previously been reported.