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

Marie Abitbol,Philippe Bossé,Stéphane Blot,Laurent Tiret,Lionel Martignat,Christophe Hitte,Anne Thomas,Nicolas Blanchard-Gutton,Vincent Mouly

doi:10.1371/journal.pone.0137019

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.

Highlights

Congenital myasthenic syndromes (CMSs) are genetically heterogeneous inherited diseases characterized by a defect in signal transmission at the neuromuscular junction (NMJ)
The COLQ NH2terminal proline-rich domain assembles the C-terminal domain of AChE; the central collagenic domain interacts with the transmembrane dystroglycan complex through the proteoglycan perlecan; the C-terminal domain interacts with the muscle-specific receptor tyrosine kinase (MuSK) and proteins of the basal lamina, yet to be identified [10,11,12]
On transverse muscle sections from the control cat, NMJs appeared normal with dense and compacted acetylcholine receptors (AchR) clusters that colocalized with aggregate acetylcholine esterase (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)

Summary

Introduction

Congenital myasthenic syndromes (CMSs) are genetically heterogeneous inherited diseases characterized by a defect in signal transmission at the neuromuscular junction (NMJ). Synaptic forms of CMSs are endplate acetylcholinesterase deficiencies mainly due to mutations in the COLQ (collagen-like tail subunit of asymmetric acetylcholinesterase) gene or more rarely, in the LAMB2 (laminin beta 2) gene (reviewed in [1]). COLQ is a key protein of the NMJ, crucial for anchoring AChE to the basal lamina through its three domains. The COLQ NH2terminal proline-rich domain assembles the C-terminal domain of AChE; the central collagenic domain interacts with the transmembrane dystroglycan complex through the proteoglycan perlecan; the C-terminal domain interacts with the muscle-specific receptor tyrosine kinase (MuSK) and proteins of the basal lamina, yet to be identified [10,11,12]

Methods

Results

Conclusion