A Novel Mutation in CLCN1 Associated with Feline Myotonia Congenita

Gandolfi, Barbara; Daniel, Rob J.; O’Brien, Dennis P.; Guo, Ling; Youngs, Melanie D.; Leach, Stacey B.; Jones, B. R.; Shelton, G. Diane; Lyons, Leslie A.

doi:10.1371/journal.pone.0109926

Cited by 18 publications

(45 citation statements)

References 54 publications

(63 reference statements)

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“…Total RNA was isolated from the retina of a sighted cat using the RNA mini kit (Invitrogen, Carlsband, CA). Complementary cDNA was synthesized as previously described (Gandolfi et al [ 64 ]). The cDNA template was subject to PCR using 10 μM of the PCR RNA forward primer (Additional file 1 : Table S2) combined with the Invitrogen polyT primer provided in the kit.…”

Section: Methodsmentioning

confidence: 99%

“…The PCR conditions were: 94 °C x 4 min followed by 10 cycles conducted at 94 °C for 10 s, 66 °C for 30 s, and 68 °C for 2 min, and 20 additional cycles at 94 °C for 10 s, 62 °C for 30 s, and 68 °C for 2 min with an additional 20 s per cycle. The PCR products with appropriate lengths were purified and sequenced using four internal primers (Additional file 1 : Table S2) as previously described [ 64 ].…”

Section: Methodsmentioning

confidence: 99%

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Whole genome sequencing in cats, identifies new models for blindness in AIPL1 and somite segmentation in HES7

et al. 2016

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BackgroundThe reduced cost and improved efficiency of whole genome sequencing (WGS) is drastically improving the development of cats as biomedical models. Persian cats are models for Leber’s congenital amaurosis (LCA), the most severe and earliest onset form of visual impairment in humans. Cats with innocuous breed-defining traits, such as a bobbed tail, can also be models for somite segmentation and vertebral column development.MethodsThe first WGS in cats was conducted on a trio segregating for LCA and the bobbed tail abnormality. Variants were identified using FreeBayes and effects predicted using SnpEff. Variants within a known haplotype block for cat LCA and specific candidate genes for both phenotypes were prioritized by the predicted variant effect on the proteins and concordant segregation within the trio. The efficiency of WGS of a single trio of domestic cats was evaluated.ResultsA stop gain was identified at position c.577C > T in cat AIPL1, a predicted p.Arg193*. A c.5A > G variant causing a p.V2A was identified in HES7. The variants segregated concordantly in a Persian – Japanese bobtail pedigree. Over 1700 cats from 40 different breeds and populations were genotyped for the AIPL1 variant, defining an allelic frequency in only Persian –related breeds of 1.15 %. A sub-set of cats was genotyped for the HES7 variant, supporting the variant as private to the Japanese bobtail breed. Approximately 18 million SNPs were identified for application in cat research. The cat AIPL1 variant would have been considered a high priority variant for evaluation, regardless of a priori knowledge from previous genetic studies.ConclusionsThis study represents the first effort of the 99 Lives Cat Genome Sequencing Initiative to identify disease - causing variants in the domestic cat using WGS. The current cat reference assembly is efficient for gene and variant identification. However, as the feline variant database improves, development of cats as biomedical models for human disease will be more efficient, providing an alternative, large animal model for drug and gene therapy trials. Undiagnosed human patients with early-onset blindness should be screened for this AIPL1 variant. The HES7 variant should further calibrate the somite segmentation clock.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-016-2595-4) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Whole genome sequencing in cats, identifies new models for blindness in AIPL1 and somite segmentation in HES7

et al. 2016

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“…Mutations in CLCN1 have been identified in Australian cattle dogs, Miniature Schnauzers, Jack Russell terrier, and cats . Mutations in SCN4A have yet to be identified in dogs.…”

Section: Myotoniamentioning

confidence: 99%

Classification of Involuntary Movements in Dogs: Myoclonus and Myotonia

Lowrie¹,

Garosi

2017

Veterinary Internal Medicne

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Myoclonus is a sudden brief, involuntary muscle jerk. Of all the movement disorders, myoclonus is the most difficult to encapsulate into any simple framework. On the one hand, a classification system is required that is clinically useful to aid in guiding diagnosis and treatment. On the other hand, there is need for a system that organizes current knowledge regarding biological mechanisms to guide scientific research. These 2 needs are distinct, making it challenging to develop a robust classification system suitable for all purposes. We attempt to classify myoclonus as “epileptic” and “nonepileptic” based on its association with epileptic seizures. Myotonia in people may be divided into 2 clinically and molecularly defined forms: (1) nondystrophic myotonias and (2) myotonic dystrophies. The former are a group of skeletal muscle channelopathies characterized by delayed skeletal muscle relaxation. Many distinct clinical phenotypes are recognized in people, the majority relating to mutations in skeletal muscle voltage‐gated chloride (CLCN1) and sodium channel (SCN4A) genes. In dogs, myotonia is associated with mutations in CLCN1. The myotonic dystrophies are considered a multisystem clinical syndrome in people encompassing 2 clinically and molecularly defined forms designated myotonic dystrophy types 1 and 2. No mutation has been linked to veterinary muscular dystrophies. We detail veterinary examples of myotonia and attempt classification according to guidelines used in humans. This more precise categorization of myoclonus and myotonia aims to promote the search for molecular markers contributing to the phenotypic spectrum of disease. Our work aimed to assist recognition for these 2 enigmatic conditions.

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“…Different degrees of myotonic symptoms can be reported among family members with identical ClC-1 mutations and among different families ( Colding-Jørgensen, 2005 ). Chloride channel myotonia also occurs in animals, including goat, mouse, dog, cat, poney, and water buffalo ( Figure 2 ; Steinmeyer et al, 1991b ; Rhodes et al, 1999 ; Wijnberg et al, 2012 ; Borges et al, 2013 ; Gandolfi et al, 2014 ). The study of myotonia in goats and mice proved to be decisive to the understanding of the pathomechanism, and eventually allowed the cloning of ClC-1 channel.…”

Section: Genetic Diseases Associated To Clc-1mentioning

confidence: 99%

ClC-1 chloride channels: state-of-the-art research and future challenges

Imbrici

Altamura

Pessia

et al. 2015

Front. Cell. Neurosci.

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The voltage-dependent ClC-1 chloride channel belongs to the CLC channel/transporter family. It is a homodimer comprising two individual pores which can operate independently or simultaneously according to two gating modes, the fast and the slow gate of the channel. ClC-1 is preferentially expressed in the skeletal muscle fibers where the presence of an efficient Cl- homeostasis is crucial for the correct membrane repolarization and propagation of action potential. As a consequence, mutations in the CLCN1 gene cause dominant and recessive forms of myotonia congenita (MC), a rare skeletal muscle channelopathy caused by abnormal membrane excitation, and clinically characterized by muscle stiffness and various degrees of transitory weakness. Elucidation of the mechanistic link between the genetic defects and the disease pathogenesis is still incomplete and, at this time, there is no specific treatment for MC. Still controversial is the subcellular localization pattern of ClC-1 channels in skeletal muscle as well as its modulation by some intracellular factors. The expression of ClC-1 in other tissues such as in brain and heart and the possible assembly of ClC-1/ClC-2 heterodimers further expand the physiological properties of ClC-1 and its involvement in diseases. A recent de novo CLCN1 truncation mutation in a patient with generalized epilepsy indeed postulates an unexpected role of this channel in the control of neuronal network excitability. This review summarizes the most relevant and state-of-the-art research on ClC-1 chloride channels physiology and associated diseases.

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A Novel Mutation in CLCN1 Associated with Feline Myotonia Congenita

Cited by 18 publications

References 54 publications

Whole genome sequencing in cats, identifies new models for blindness in AIPL1 and somite segmentation in HES7

Whole genome sequencing in cats, identifies new models for blindness in AIPL1 and somite segmentation in HES7

Classification of Involuntary Movements in Dogs: Myoclonus and Myotonia

ClC-1 chloride channels: state-of-the-art research and future challenges

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