Limits...
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

Pedigree-tree of a Sphynx cat family segregating a neuromuscular disorder.Circles represent females, squares represent males. Affected kittens are depicted with fully filled symbols and the proband shown with an arrow. Healthy carriers are depicted with two-toned symbols. Red symbols represent the seven cats from the nuclear family used to map the disease locus; blue symbols represent the four healthy siblings of the proband and the 16 healthy cats directly related to the sire; black symbols represent cats from the extended family. When available, result of the genotyping assay for the c.1190G>A variant is mentioned. The Devon Rex female born in 1990 and known by breeders to have several myopathy healthy carriers in her pedigree is shown (Devon Rex).
© Copyright Policy
Related In: Results  -  Collection

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

pone.0137019.g003: Pedigree-tree of a Sphynx cat family segregating a neuromuscular disorder.Circles represent females, squares represent males. Affected kittens are depicted with fully filled symbols and the proband shown with an arrow. Healthy carriers are depicted with two-toned symbols. Red symbols represent the seven cats from the nuclear family used to map the disease locus; blue symbols represent the four healthy siblings of the proband and the 16 healthy cats directly related to the sire; black symbols represent cats from the extended family. When available, result of the genotyping assay for the c.1190G>A variant is mentioned. The Devon Rex female born in 1990 and known by breeders to have several myopathy healthy carriers in her pedigree is shown (Devon Rex).

Mentions: Both parents were healthy; they subsequently produced three other litters yielding one affected male (S1 Fig), nine unaffected cats and a female that died precociously from asphyxia at three weeks of age. Healthy parents and affected kittens supported the autosomal recessive inheritance pattern previously reported for this neuromuscular disorder (Fig 3; [13]). Pedigree examination of the two parents revealed ancestors from the Devon Rex breed, which had previously been identified as carriers of the Devon Rex neuromuscular disorder [15, 26]. In addition, some of these Devon Rex ancestors were shared by the sire and dam of the affected Sphynx cats reported in the present study (Fig 3).


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)

Pedigree-tree of a Sphynx cat family segregating a neuromuscular disorder.Circles represent females, squares represent males. Affected kittens are depicted with fully filled symbols and the proband shown with an arrow. Healthy carriers are depicted with two-toned symbols. Red symbols represent the seven cats from the nuclear family used to map the disease locus; blue symbols represent the four healthy siblings of the proband and the 16 healthy cats directly related to the sire; black symbols represent cats from the extended family. When available, result of the genotyping assay for the c.1190G>A variant is mentioned. The Devon Rex female born in 1990 and known by breeders to have several myopathy healthy carriers in her pedigree is shown (Devon Rex).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4556666&req=5

pone.0137019.g003: Pedigree-tree of a Sphynx cat family segregating a neuromuscular disorder.Circles represent females, squares represent males. Affected kittens are depicted with fully filled symbols and the proband shown with an arrow. Healthy carriers are depicted with two-toned symbols. Red symbols represent the seven cats from the nuclear family used to map the disease locus; blue symbols represent the four healthy siblings of the proband and the 16 healthy cats directly related to the sire; black symbols represent cats from the extended family. When available, result of the genotyping assay for the c.1190G>A variant is mentioned. The Devon Rex female born in 1990 and known by breeders to have several myopathy healthy carriers in her pedigree is shown (Devon Rex).
Mentions: Both parents were healthy; they subsequently produced three other litters yielding one affected male (S1 Fig), nine unaffected cats and a female that died precociously from asphyxia at three weeks of age. Healthy parents and affected kittens supported the autosomal recessive inheritance pattern previously reported for this neuromuscular disorder (Fig 3; [13]). Pedigree examination of the two parents revealed ancestors from the Devon Rex breed, which had previously been identified as carriers of the Devon Rex neuromuscular disorder [15, 26]. In addition, some of these Devon Rex ancestors were shared by the sire and dam of the affected Sphynx cats reported in the present study (Fig 3).

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