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A COLQ Missense Mutation in Sphynx and Devon Rex Cats with Congenital Myasthenic Syndrome.

Abitbol M, Hitte C, Bossé P, Blanchard-Gutton N, Thomas A, Martignat L, Blot S, Tiret L - PLoS ONE (2015)

Bottom Line: Segregation of the c.1190G>A variant was 100% consistent with the autosomal recessive mode of inheritance of the disorder in our cat pedigree; in addition, an affected, unrelated Devon Rex cat recruited thereafter was also homozygous for the variant.Altogether, these results strongly support that the neuromuscular disorder reported in Sphynx and Devon Rex breeds is a CMS caused by a unique c.1190G>A missense mutation, presumably transmitted through a founder effect, which strictly and slightly disseminated in these two breeds.The presently available DNA test will help owners avoid matings at risk.

View Article: PubMed Central - PubMed

Affiliation: Inserm, IMRB U955-E10, 94000, Créteil, France; Université Paris Est, Ecole nationale vétérinaire d'Alfort, 94700, Maisons-Alfort, & Faculté de médecine, 94000, Créteil, France; Etablissement Français du Sang, 94017, Créteil, France; APHP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy & Centre de référence des maladies neuromusculaires GNMH, 94000 Créteil, France.

ABSTRACT
An autosomal recessive neuromuscular disorder characterized by skeletal muscle weakness, fatigability and variable electromyographic or muscular histopathological features has been described in the two related Sphynx and Devon Rex cat breeds (Felis catus). Collection of data from two affected Sphynx cats and their relatives pointed out a single disease candidate region on feline chromosome C2, identified following a genome-wide SNP-based homozygosity mapping strategy. In that region, we further identified COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase) as a good candidate gene, since COLQ mutations were identified in affected humans and dogs with endplate acetylcholinesterase deficiency leading to a synaptic form of congenital myasthenic syndrome (CMS). A homozygous c.1190G>A missense variant located in exon 15 of COLQ, leading to a C397Y substitution, was identified in the two affected cats. C397 is a highly-conserved residue from the C-terminal domain of the protein; its mutation was previously shown to produce CMS in humans, and here we confirmed in an affected Sphynx cat that it induces a loss of acetylcholinesterase clustering at the neuromuscular junction. Segregation of the c.1190G>A variant was 100% consistent with the autosomal recessive mode of inheritance of the disorder in our cat pedigree; in addition, an affected, unrelated Devon Rex cat recruited thereafter was also homozygous for the variant. Genotyping of a panel of 333 cats from 14 breeds failed to identify a single carrier in non-Sphynx and non-Devon Rex cats. Finally, the percentage of healthy carriers in a European subpanel of 81 genotyped Sphynx cats was estimated to be low (3.7%) and 14 control Devon Rex cats were genotyped as wild-type individuals. Altogether, these results strongly support that the neuromuscular disorder reported in Sphynx and Devon Rex breeds is a CMS caused by a unique c.1190G>A missense mutation, presumably transmitted through a founder effect, which strictly and slightly disseminated in these two breeds. The presently available DNA test will help owners avoid matings at risk.

No MeSH data available.


Related in: MedlinePlus

Congenital neuromuscular disorder in a Sphynx kitten.Picture of the four-month-old Sphynx female kitten presented at the Neurology clinics located at the Alfort School of Veterinary Medicine campus, in Maisons-Alfort, France. The kitten displayed a peculiar gait while walking, with ventroflexion of her neck. Note the marked dorsal protrusion of scapulae. No significant muscle atrophy was noticed.
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pone.0137019.g001: Congenital neuromuscular disorder in a Sphynx kitten.Picture of the four-month-old Sphynx female kitten presented at the Neurology clinics located at the Alfort School of Veterinary Medicine campus, in Maisons-Alfort, France. The kitten displayed a peculiar gait while walking, with ventroflexion of her neck. Note the marked dorsal protrusion of scapulae. No significant muscle atrophy was noticed.

Mentions: In 2007, a four-month-old female proband kitten from the Sphynx breed showing reduced activity and weakness was presented with her unique littermate (female) at the Neurological clinics located at the Alfort School of Veterinary Medicine in Maisons-Alfort, France. Onset of clinical signs had started a month before presentation, with reduced activity, weakness and slightly after, abnormal postures and locomotion. The affected kitten needed frequent resting periods when playing. During the clinical evaluation, no muscle atrophy was noticed; she however displayed a peculiar gait while walking, with shoulder blades held high and ventroflexion of the neck. At both rest or during walking, she displayed a marked dorsal protrusion of scapulae (Fig 1). After short playing sequences with her littermate, the affected female showed a “dog-begging” position, with front legs resting on a stair. Exercise was followed by stride shortening and limb tremors. The breeder also reported difficulties in taking and swallowing food, as well as occasional choking episodes while eating. During these acute sequences, food was placed on a raised platform and the breeder supervised its cat to prevent possible suffocation from swallowed food into the trachea. Neurological examination was normal in the affected female and her littermate, including normal responses of cranial and appendicular nerves. Electromyographic recording revealed a weak, slightly abnormal spontaneous activity within the tibialis anterior of the affected female, with normal velocities of tibial and ulnar nerves. Repetitive stimulation was not performed. Blood count, routine serum biochemical parameters and creatine kinase activity were all within reference ranges for the two littermates. Biopsies of the cervical, triceps brachii and biceps femoris muscles were performed in the two cats. Muscles from the healthy littermate displayed normal features on histological and histo-enzymological sections (Fig 2 and S2 Fig). By contrast, sections of the cervical muscle sampled from the affected female showed the most prominent abnormalities, including fibre size and shape variation; most of myofibres appeared round and atrophic or hypertrophic. Muscle spindles could be observed and were unremarkable, as were intramuscular nerves which density and myelin thickness seemed normal. Fibres were all well differentiated. No topographic aggregation for type-1 or type-2 fibres was noticed (Fig 2). Molecular components of NMJs were stained using a fluorescent alpha-bungarotoxin (postsynaptic acetylcholine receptor AchR) or acetylcholine esterase activity (synaptic AchE). On transverse muscle sections from the control cat, NMJs appeared normal with dense and compacted AchR clusters that colocalized with aggregate AchE activity; by contrast, NMJs of myofibres from the affected Sphynx littermate revealed an abnormal, dispersed AchE staining, with normal clustering of AchR (Fig 2).


A COLQ Missense Mutation in Sphynx and Devon Rex Cats with Congenital Myasthenic Syndrome.

Abitbol M, Hitte C, Bossé P, Blanchard-Gutton N, Thomas A, Martignat L, Blot S, Tiret L - PLoS ONE (2015)

Congenital neuromuscular disorder in a Sphynx kitten.Picture of the four-month-old Sphynx female kitten presented at the Neurology clinics located at the Alfort School of Veterinary Medicine campus, in Maisons-Alfort, France. The kitten displayed a peculiar gait while walking, with ventroflexion of her neck. Note the marked dorsal protrusion of scapulae. No significant muscle atrophy was noticed.
© Copyright Policy
Related In: Results  -  Collection

License
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getmorefigures.php?uid=PMC4556666&req=5

pone.0137019.g001: Congenital neuromuscular disorder in a Sphynx kitten.Picture of the four-month-old Sphynx female kitten presented at the Neurology clinics located at the Alfort School of Veterinary Medicine campus, in Maisons-Alfort, France. The kitten displayed a peculiar gait while walking, with ventroflexion of her neck. Note the marked dorsal protrusion of scapulae. No significant muscle atrophy was noticed.
Mentions: In 2007, a four-month-old female proband kitten from the Sphynx breed showing reduced activity and weakness was presented with her unique littermate (female) at the Neurological clinics located at the Alfort School of Veterinary Medicine in Maisons-Alfort, France. Onset of clinical signs had started a month before presentation, with reduced activity, weakness and slightly after, abnormal postures and locomotion. The affected kitten needed frequent resting periods when playing. During the clinical evaluation, no muscle atrophy was noticed; she however displayed a peculiar gait while walking, with shoulder blades held high and ventroflexion of the neck. At both rest or during walking, she displayed a marked dorsal protrusion of scapulae (Fig 1). After short playing sequences with her littermate, the affected female showed a “dog-begging” position, with front legs resting on a stair. Exercise was followed by stride shortening and limb tremors. The breeder also reported difficulties in taking and swallowing food, as well as occasional choking episodes while eating. During these acute sequences, food was placed on a raised platform and the breeder supervised its cat to prevent possible suffocation from swallowed food into the trachea. Neurological examination was normal in the affected female and her littermate, including normal responses of cranial and appendicular nerves. Electromyographic recording revealed a weak, slightly abnormal spontaneous activity within the tibialis anterior of the affected female, with normal velocities of tibial and ulnar nerves. Repetitive stimulation was not performed. Blood count, routine serum biochemical parameters and creatine kinase activity were all within reference ranges for the two littermates. Biopsies of the cervical, triceps brachii and biceps femoris muscles were performed in the two cats. Muscles from the healthy littermate displayed normal features on histological and histo-enzymological sections (Fig 2 and S2 Fig). By contrast, sections of the cervical muscle sampled from the affected female showed the most prominent abnormalities, including fibre size and shape variation; most of myofibres appeared round and atrophic or hypertrophic. Muscle spindles could be observed and were unremarkable, as were intramuscular nerves which density and myelin thickness seemed normal. Fibres were all well differentiated. No topographic aggregation for type-1 or type-2 fibres was noticed (Fig 2). Molecular components of NMJs were stained using a fluorescent alpha-bungarotoxin (postsynaptic acetylcholine receptor AchR) or acetylcholine esterase activity (synaptic AchE). On transverse muscle sections from the control cat, NMJs appeared normal with dense and compacted AchR clusters that colocalized with aggregate AchE activity; by contrast, NMJs of myofibres from the affected Sphynx littermate revealed an abnormal, dispersed AchE staining, with normal clustering of AchR (Fig 2).

Bottom Line: Segregation of the c.1190G>A variant was 100% consistent with the autosomal recessive mode of inheritance of the disorder in our cat pedigree; in addition, an affected, unrelated Devon Rex cat recruited thereafter was also homozygous for the variant.Altogether, these results strongly support that the neuromuscular disorder reported in Sphynx and Devon Rex breeds is a CMS caused by a unique c.1190G>A missense mutation, presumably transmitted through a founder effect, which strictly and slightly disseminated in these two breeds.The presently available DNA test will help owners avoid matings at risk.

View Article: PubMed Central - PubMed

Affiliation: Inserm, IMRB U955-E10, 94000, Créteil, France; Université Paris Est, Ecole nationale vétérinaire d'Alfort, 94700, Maisons-Alfort, & Faculté de médecine, 94000, Créteil, France; Etablissement Français du Sang, 94017, Créteil, France; APHP, Hôpitaux Universitaires Henri Mondor, DHU Pepsy & Centre de référence des maladies neuromusculaires GNMH, 94000 Créteil, France.

ABSTRACT
An autosomal recessive neuromuscular disorder characterized by skeletal muscle weakness, fatigability and variable electromyographic or muscular histopathological features has been described in the two related Sphynx and Devon Rex cat breeds (Felis catus). Collection of data from two affected Sphynx cats and their relatives pointed out a single disease candidate region on feline chromosome C2, identified following a genome-wide SNP-based homozygosity mapping strategy. In that region, we further identified COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase) as a good candidate gene, since COLQ mutations were identified in affected humans and dogs with endplate acetylcholinesterase deficiency leading to a synaptic form of congenital myasthenic syndrome (CMS). A homozygous c.1190G>A missense variant located in exon 15 of COLQ, leading to a C397Y substitution, was identified in the two affected cats. C397 is a highly-conserved residue from the C-terminal domain of the protein; its mutation was previously shown to produce CMS in humans, and here we confirmed in an affected Sphynx cat that it induces a loss of acetylcholinesterase clustering at the neuromuscular junction. Segregation of the c.1190G>A variant was 100% consistent with the autosomal recessive mode of inheritance of the disorder in our cat pedigree; in addition, an affected, unrelated Devon Rex cat recruited thereafter was also homozygous for the variant. Genotyping of a panel of 333 cats from 14 breeds failed to identify a single carrier in non-Sphynx and non-Devon Rex cats. Finally, the percentage of healthy carriers in a European subpanel of 81 genotyped Sphynx cats was estimated to be low (3.7%) and 14 control Devon Rex cats were genotyped as wild-type individuals. Altogether, these results strongly support that the neuromuscular disorder reported in Sphynx and Devon Rex breeds is a CMS caused by a unique c.1190G>A missense mutation, presumably transmitted through a founder effect, which strictly and slightly disseminated in these two breeds. The presently available DNA test will help owners avoid matings at risk.

No MeSH data available.


Related in: MedlinePlus