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

Genotypes for chromosome C2 candidate region.SNP genotypes for each cat were manually inspected in Excel to identify homozygous regions shared by the two affected cats. Only one region from chromosome C2 spanning from position 137108027 bp to position 140984522 bp (according to the updated felCat5 SNP manifest for the Illumina Feline 63k SNP genotyping array, [20]) was consistent with the highly-probable heterozygous status of the sire and dam, the non-homozygously mutated status of the proband’s healthy littermate and the inferred heterozygous status of the paternal grandmother. This region encompassed 3.9 Mb. Homozygosity for the allele shared by the affected sib-pair is shown in light green. Heterozygosity or homozygosity for the opposite allele is shown in yellow. Missing genotypes are noticed 0. Chr: chromosome. bp: base pairs.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0137019.g004: Genotypes for chromosome C2 candidate region.SNP genotypes for each cat were manually inspected in Excel to identify homozygous regions shared by the two affected cats. Only one region from chromosome C2 spanning from position 137108027 bp to position 140984522 bp (according to the updated felCat5 SNP manifest for the Illumina Feline 63k SNP genotyping array, [20]) was consistent with the highly-probable heterozygous status of the sire and dam, the non-homozygously mutated status of the proband’s healthy littermate and the inferred heterozygous status of the paternal grandmother. This region encompassed 3.9 Mb. Homozygosity for the allele shared by the affected sib-pair is shown in light green. Heterozygosity or homozygosity for the opposite allele is shown in yellow. Missing genotypes are noticed 0. Chr: chromosome. bp: base pairs.

Mentions: Genome wide association studies using single nucleotide polymorphism (SNP) arrays have proved a successful approach to identify recessive mutations in felines when cohorts of several affected cases and controls are available [27, 28]. In the present study, only two affected cats were available. To circumvent this limitation, we used an homozygosity mapping strategy in our nuclear family. The affected sib-pair, the healthy littermate of the proband, their two healthy parents and the two paternal grandparents were genotyped using the Illumina Feline 63k SNP array, among which 61,705 SNPs yielded usable results. The seven cats had genotyping rates > 95% and were all conserved for the analysis. Genotypes for each chromosome were manually inspected to identify homozygous regions shared by the two affected cats. Six regions located on chromosomes A3, B3, C1, C2, D1 and E1 were identified (S2 Table). Only one region from chromosome C2 was consistent with the highly probable heterozygous status of the two parents, the non-homozygously mutated status of the proband's healthy littermate and the inferred heterozygous status of the paternal grandmother; this region encompassed 3.9 Mb (Fig 4). Comparison of genes within or in the vicinity of the identified region with a reference list of genes possibly causing neuromuscular disorders when mutated [29] revealed COLQ as the closest presumptive candidate gene (chromosome C2: 133071353–133148521 bp, GenBank ID: 101093134, Felis_catus 8.0 GenBank assembly, annotation release 102). According to the felCat5 SNP manifest based on the Felis_catus 6.2 GenBank assembly [20], the identified candidate region on chromosome C2 was lying 3.9 Mb from COLQ. Inconsistencies between versions of the feline genome assembly, on the one hand, and between genomic locations of SNPs from the Illumina 63k array and versions of the genome assembly, on the other hand [20], led us to still consider COLQ as a good candidate gene.


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)

Genotypes for chromosome C2 candidate region.SNP genotypes for each cat were manually inspected in Excel to identify homozygous regions shared by the two affected cats. Only one region from chromosome C2 spanning from position 137108027 bp to position 140984522 bp (according to the updated felCat5 SNP manifest for the Illumina Feline 63k SNP genotyping array, [20]) was consistent with the highly-probable heterozygous status of the sire and dam, the non-homozygously mutated status of the proband’s healthy littermate and the inferred heterozygous status of the paternal grandmother. This region encompassed 3.9 Mb. Homozygosity for the allele shared by the affected sib-pair is shown in light green. Heterozygosity or homozygosity for the opposite allele is shown in yellow. Missing genotypes are noticed 0. Chr: chromosome. bp: base pairs.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0137019.g004: Genotypes for chromosome C2 candidate region.SNP genotypes for each cat were manually inspected in Excel to identify homozygous regions shared by the two affected cats. Only one region from chromosome C2 spanning from position 137108027 bp to position 140984522 bp (according to the updated felCat5 SNP manifest for the Illumina Feline 63k SNP genotyping array, [20]) was consistent with the highly-probable heterozygous status of the sire and dam, the non-homozygously mutated status of the proband’s healthy littermate and the inferred heterozygous status of the paternal grandmother. This region encompassed 3.9 Mb. Homozygosity for the allele shared by the affected sib-pair is shown in light green. Heterozygosity or homozygosity for the opposite allele is shown in yellow. Missing genotypes are noticed 0. Chr: chromosome. bp: base pairs.
Mentions: Genome wide association studies using single nucleotide polymorphism (SNP) arrays have proved a successful approach to identify recessive mutations in felines when cohorts of several affected cases and controls are available [27, 28]. In the present study, only two affected cats were available. To circumvent this limitation, we used an homozygosity mapping strategy in our nuclear family. The affected sib-pair, the healthy littermate of the proband, their two healthy parents and the two paternal grandparents were genotyped using the Illumina Feline 63k SNP array, among which 61,705 SNPs yielded usable results. The seven cats had genotyping rates > 95% and were all conserved for the analysis. Genotypes for each chromosome were manually inspected to identify homozygous regions shared by the two affected cats. Six regions located on chromosomes A3, B3, C1, C2, D1 and E1 were identified (S2 Table). Only one region from chromosome C2 was consistent with the highly probable heterozygous status of the two parents, the non-homozygously mutated status of the proband's healthy littermate and the inferred heterozygous status of the paternal grandmother; this region encompassed 3.9 Mb (Fig 4). Comparison of genes within or in the vicinity of the identified region with a reference list of genes possibly causing neuromuscular disorders when mutated [29] revealed COLQ as the closest presumptive candidate gene (chromosome C2: 133071353–133148521 bp, GenBank ID: 101093134, Felis_catus 8.0 GenBank assembly, annotation release 102). According to the felCat5 SNP manifest based on the Felis_catus 6.2 GenBank assembly [20], the identified candidate region on chromosome C2 was lying 3.9 Mb from COLQ. Inconsistencies between versions of the feline genome assembly, on the one hand, and between genomic locations of SNPs from the Illumina 63k array and versions of the genome assembly, on the other hand [20], led us to still consider COLQ as a good candidate gene.

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