Carrier Rate and Mutant Allele Frequency of GM1 Gangliosidosis in Miniature Shiba Inus (Mame Shiba): Population Screening of Breeding Dogs in Japan

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Niemann–Pick disease (NP) type C is an autosomal, recessive, and inherited neurovisceral genetic disorder characterized by the accumulation of unesterified cholesterol and glycolipids in cellular lysosomes and late endosomes, with a wide spectrum of clinical phenotypes. This study aimed to determine the molecular genetic alterations in two cases of felines with NP in Japan, a Siamese cat in 1989 and a Japanese domestic (JD) cat in 1998. Sanger sequencing was performed on 25 exons of the feline NPC1 gene and 4 exons of the feline NPC2 gene, using genomic DNA extracted from paraffin-embedded tissue specimens. The sequenced exons were compared with reference sequences retrieved from the GenBank database. The identified mutations and alterations were then analyzed using different prediction algorithms. No pathogenic mutations were found in feline NPC1; however, c.376G>A (p.V126M) was identified as a pathogenic mutation in the NPC2 gene. The Siamese cat was found to be homozygous for this mutation. The JD cat was heterozygous for the same mutation, but no other exonic NPC2 mutation was found. Furthermore, the JD cat had a homozygous splice variant (c.364-4C>T) in the NPC2 gene, which is not known to be associated with this disease. The NPC2:c.376G>A (p.V126M) mutation is the second reported pathogenic mutation in the feline NPC2 gene that may be present in the Japanese cat population.

Section: Discussionmentioning

confidence: 99%

Novel Mutation in the Feline NPC2 Gene in Cats with Niemann–Pick Disease

Rakib

Islam

Uddin

et al. 2023

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Section: Discussionmentioning

confidence: 99%

“…In Japan, molecular epidemiological surveys have been carried out for several inherited canine diseases to determine the associated mutant allele frequencies and thereby evaluate the necessity of prevention measures [27][28][29][30][31]. Among these, lethal diseases characterized by progressive neurological dysfunction include GM1 gangliosidosis in Shiba Inus (mutant allele frequency = 0.00509) [27] and Mame Shibas (0.00246) [28], neuronal ceroid lipofuscinosis (NCL) in Chihuahuas (0.00645) [30], Sandhoff disease in Toy Poodles (0.00101) [29], and NCL in Border Collies (0.0405) [31]. Compared with the mutant allele frequencies in these lethal diseases with juvenile, late juvenile, or early adult onset [32], DM had particularly high mutant allele frequencies in PWCs (0.697) and Collies (0.138) [10,21] as well as GSDs (0.220) in this study, although there was a notably large difference in frequency among these three breeds (Table 2).…”

Section: Discussionmentioning

confidence: 99%

Molecular Epidemiological Survey for Degenerative Myelopathy in German Shepherd Dogs in Japan: Allele Frequency and Clinical Progression Rate

Maki

Islam

Itoh

et al. 2022

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Canine degenerative myelopathy (DM) is an adult-onset, chronic, progressive neurodegenerative disease reported in multiple canine breeds, including the German Shepherd Dog (GSD). Clinical signs include progressive motor neuron paralysis, which begins in the pelvic limbs and eventually leads to respiratory distress, which may necessitate euthanasia. A common DM-associated mutation is a single nucleotide substitution that causes an amino acid substitution (c.118G>A, p.E40K) in the canine SOD1 gene. This SOD1 mutation and the clinical progression rate of A/A risk genotype in the Japanese GSD population have not been analyzed before. Therefore, the aim of this study was to determine the frequency of the mutated allele and analyze the clinical progression rate in the Japanese GSD population. We studied 541 GSDs registered with the Japanese German Shepherd Dog Registration Society between 2000 and 2019. Genotyping was performed using real-time PCR with DNA extracted from the hair roots of each dog. The study revealed 330 G/G dogs (61%), 184 G/A dogs (34%), and 27 A/A dogs (5%), indicating a frequency of the mutant allele of 0.220, which are in Hardy–Weinberg equilibrium. We analyzed the clinical signs in A/A dogs with an age limit of 10 years based on information obtained from the dogs’ owners. Of the seven A/A dogs older than 10 years, owners reported DM-related clinical signs, indicating a clinical progression rate of 100%. These results, further genotyping, and thorough clinical examinations of SOD1 A/A risk genotype will help control and prevent DM in the Japanese GSD population.

“…A loss of β-galactosidase activity is also noted [86,87]. In Portuguese Water Dogs, the identified variant was a G to A transition in the exon 2 of the GLB1 gene, while, in the Shiba Inu and Miniature Shiba Inu, the identified variant was a deletion of a single bp (cytosine) in exon 15 of the same GLB1 gene [88][89][90]. In the Alaskan Husky, the causal variant associated with GM1 gangliosidosis was a 19 bp insertion (duplication) in exon 15 of the GLB1 gene [91].…”

Section: Lysosomal Storage Disordersmentioning

confidence: 99%

An Overview of Canine Inherited Neurological Disorders with Known Causal Variants

Cocostîrc,

Paștiu,

Pusta

2023

Hereditary neurological conditions documented in dogs encompass congenital, neonatal, and late-onset disorders, along with both progressive and non-progressive forms. In order to identify the causal variant of a disease, the main two approaches are genome-wide investigations and candidate gene investigation. Online Mendelian Inheritance in Animals currently lists 418 Mendelian disorders specific to dogs, of which 355 have their likely causal genetic variant identified. This review aims to summarize the current knowledge on the canine nervous system phenes and their genetic causal variant. It has been noted that the majority of these diseases have an autosomal recessive pattern of inheritance. Additionally, the dog breeds that are more prone to develop such diseases are the Golden Retriever, in which six inherited neurological disorders with a known causal variant have been documented, and the Belgian Shepherd, in which five such disorders have been documented. DNA tests can play a vital role in effectively managing and ultimately eradicating inherited diseases.