A large intragenic deletion in the CLCN1 gene causes Hereditary Myotonia in pigs

Abstract

Mutations in the CLCN1 gene are the primary cause of non-dystrophic Hereditary Myotonia in several animal species. However, there are no reports of Hereditary Myotonia in pigs to date. Therefore, the objective of the present study was to characterize the clinical and molecular findings of Hereditary Myotonia in an inbred pedigree. The clinical, electromyographic, histopathological, and molecular findings were evaluated. Clinically affected pigs presented non-dystrophic recessive Hereditary Myotonia. Nucleotide sequence analysis of the entire coding region of the CLCN1 gene revealed the absence of the exons 15 and 16 in myotonic animals. Analysis of the genomic region flanking the deletion unveiled a large intragenic deletion of 4,165 nucleotides. Interestingly, non-related, non-myotonic pigs expressed transcriptional levels of an alternate transcript (i.e., X2) that was identical to the deleted X1 transcript of myotonic pigs. All myotonic pigs and their progenitors were homozygous recessive and heterozygous, respectively, for the 4,165-nucleotide deletion. This is the first study reporting Hereditary Myotonia in pigs and characterizing its clinical and molecular findings. Moreover, to the best of our knowledge, Hereditary Myotonia has never been associated with a genomic deletion in the CLCN1 gene in any other species.

A complex CLCN1 variant associated with hereditary myotonia in a mixed-breed dog

“…12,15,17 The diagnosis was confirmed through electromyography, which showed myotonic discharges in the thoracic limbs, pelvic limbs, and tongue muscles, especially in the pelvic limbs. 1,12,17,20 The patient did not exhibit upper airway stridor or continuous wheezing sounds, which are also reported in some dogs with myotonia.…”

“…Clinical signs of HM have been documented in goats, 4,5 horses, 14 cats, 9,22 dogs, 7,8,12,20 buffaloes, 3 and pigs. 1 Clinical signs are characterized by muscle stiffness after initiation of movement (or startle) and a bunny-hop type movement when running, with gait improvement after warm-up. 20,22 Nonpainful muscle spasms, generalized muscle hypertrophy, and episodes of recumbency after stimulation can also be observed.…”

“…DNA tests based on the PCR technique, used for screening in breeds known to have this disease, can be adopted as a detection tool. The CLCN1 mutations responsible for congenital myotonia in animals have been described in rats, 19 buffaloes, 3 pigs, 1 horse, 21 sheep, 13 and cats. 9,22 Six studies have described CLCN1 mutations in dogs, namely in the Miniature Schnauzer 2,16 and Jack Russell Terrier 12 (C to T transition in the ClC-1 allele), Australian Cattle dog (insertion of a single [deoxy] adenylate at position 2665 in CLCN1 ), 8 Labrador Retriever (variant c.2275A>T in CLCN1 ), 15 and the American Bulldog (frameshift mutation c.436_437insCTCT in CLCN1 ).…”

A novel mutation of the CLCN1 gene in a cat with myotonia congenita: Diagnosis and treatment

“… 1 , 2 Disorders causing myotonia are divided into dystrophic and nondystrophic categories. 2 , 3 , 4 , 5 The nondystrophic myotonias include chloride and sodium channelopathies, and chloride channelopathies, referred to as myotonia congenita, have been reported in many species including mice, 6 dogs, 1 cats, 7 , 8 , 9 pigs, 10 cattle, 11 horses, 12 , 13 goats, 14 , 15 and humans. 3 The first discovery of a mutation within CLCN1 , a gene that encodes a voltage‐gated chloride channel (ClC‐1), occurred in the goat.…”

Hereditary myotonia in cats associated with a new homozygous missense variant p.Ala331Pro in the muscle chloride channel ClC‐1

“…Hereditary nondystrophic myotonia associated with chloride voltage‐gated channel 1 ( CLCN1 ) gene mutations occurs in goats, 1 dogs, 2‐6 horses, 7 buffalos, 8 sheep, 9 and pigs 10 . Myotonia occurs in cats, 11‐13 and a mutation associated with this disease in this species is identified 14,15 .…”