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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

Wild-type and mutant C-terminal domains of COLQ proteins.Alignment of partial protein sequences of COLQ, translated from the c.[1190G>A] mutated allele identified in affected Sphynx and Rex Devon cats (Felis MUT) or wild-type alleles reported in human (Homo), mouse (Mus), cow (Bos), chicken (Gallus), xenopus (Xenopus), zebrafish (Danio), fugu (Taxifugu) and cat (Felis WT). The cysteine-rich domain of the C-terminal end of the protein starts with amino acid number 375 in human and cat proteins and ends with amino acid number 451 (according to [10]). Human COLQ sequence was used as the reference sequence. Conserved residues are written in red within the reference sequence and represented by red dots in other sequences. Dashes represent deletions. Arrows point out the ten conserved cysteine residues. Cysteine 397, mutated in affected cats (C397Y), is surrounded in blue.
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pone.0137019.g005: Wild-type and mutant C-terminal domains of COLQ proteins.Alignment of partial protein sequences of COLQ, translated from the c.[1190G>A] mutated allele identified in affected Sphynx and Rex Devon cats (Felis MUT) or wild-type alleles reported in human (Homo), mouse (Mus), cow (Bos), chicken (Gallus), xenopus (Xenopus), zebrafish (Danio), fugu (Taxifugu) and cat (Felis WT). The cysteine-rich domain of the C-terminal end of the protein starts with amino acid number 375 in human and cat proteins and ends with amino acid number 451 (according to [10]). Human COLQ sequence was used as the reference sequence. Conserved residues are written in red within the reference sequence and represented by red dots in other sequences. Dashes represent deletions. Arrows point out the ten conserved cysteine residues. Cysteine 397, mutated in affected cats (C397Y), is surrounded in blue.

Mentions: To evaluate the functional importance of the C397 residue, we aligned the feline COLQ protein sequence with the COLQ sequences of seven vertebrates (Fig 5 and S2 Fig). We found a 87% identity between feline and human COLQ proteins and a full conservation of the C397 residue between the seven COLQ sequences. This high level of conservation was previously reported for the 10 essential cysteines of the cysteine-rich domain of COLQ C-terminal region, spanning from residues 375 to 451 in the human protein [10–12]. In addition, the feline C397 residue of COLQ best aligns with C397 of its human ortholog (Fig 5 and S2 Fig), found to be mutated in human patients affected by endplate AChE deficiency (i.e. synaptic CMS) [10–12].


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)

Wild-type and mutant C-terminal domains of COLQ proteins.Alignment of partial protein sequences of COLQ, translated from the c.[1190G>A] mutated allele identified in affected Sphynx and Rex Devon cats (Felis MUT) or wild-type alleles reported in human (Homo), mouse (Mus), cow (Bos), chicken (Gallus), xenopus (Xenopus), zebrafish (Danio), fugu (Taxifugu) and cat (Felis WT). The cysteine-rich domain of the C-terminal end of the protein starts with amino acid number 375 in human and cat proteins and ends with amino acid number 451 (according to [10]). Human COLQ sequence was used as the reference sequence. Conserved residues are written in red within the reference sequence and represented by red dots in other sequences. Dashes represent deletions. Arrows point out the ten conserved cysteine residues. Cysteine 397, mutated in affected cats (C397Y), is surrounded in blue.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0137019.g005: Wild-type and mutant C-terminal domains of COLQ proteins.Alignment of partial protein sequences of COLQ, translated from the c.[1190G>A] mutated allele identified in affected Sphynx and Rex Devon cats (Felis MUT) or wild-type alleles reported in human (Homo), mouse (Mus), cow (Bos), chicken (Gallus), xenopus (Xenopus), zebrafish (Danio), fugu (Taxifugu) and cat (Felis WT). The cysteine-rich domain of the C-terminal end of the protein starts with amino acid number 375 in human and cat proteins and ends with amino acid number 451 (according to [10]). Human COLQ sequence was used as the reference sequence. Conserved residues are written in red within the reference sequence and represented by red dots in other sequences. Dashes represent deletions. Arrows point out the ten conserved cysteine residues. Cysteine 397, mutated in affected cats (C397Y), is surrounded in blue.
Mentions: To evaluate the functional importance of the C397 residue, we aligned the feline COLQ protein sequence with the COLQ sequences of seven vertebrates (Fig 5 and S2 Fig). We found a 87% identity between feline and human COLQ proteins and a full conservation of the C397 residue between the seven COLQ sequences. This high level of conservation was previously reported for the 10 essential cysteines of the cysteine-rich domain of COLQ C-terminal region, spanning from residues 375 to 451 in the human protein [10–12]. In addition, the feline C397 residue of COLQ best aligns with C397 of its human ortholog (Fig 5 and S2 Fig), found to be mutated in human patients affected by endplate AChE deficiency (i.e. synaptic CMS) [10–12].

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