Molecular cloning of ion channels inFelis catusthat are related to periodic paralyses in man: a contribution to the understanding of the genetic susceptibility to feline neck ventroflexion and paralysis

Abstract

Neck ventroflexion in cats has different causes; however, the most common is the hypokalemia associated with flaccid paralysis secondary to chronic renal failure. In humans, the most common causes of acute flaccid paralysis are hypokalemia precipitated by thyrotoxicosis and familial forms linked to mutations in sodium, potassium, and calcium channel genes. Here, we describe the sequencing and analysis of skeletal muscle ion channels in Felis catus that could be related to periodic paralyses in humans, contributing to the understanding of the genetic susceptibility to feline neck ventroflexion and paralysis. We studied genomic DNA from eleven cats, including five animals that were hyperthyroid with hypokalemia, although only one presented with muscle weakness, and six healthy control domestic cats. We identified the ion channel ortholog genes KCNJ2, KCNJ12, KCNJ14, CACNA1S and SCN4A in the Felis catus genome, together with several polymorphic variants. Upon comparative alignment with other genomes, we found that Felis catus provides evidence for a high genomic conservation of ion channel sequences. Although we hypothesized that neck ventroflexion in cats could be associated with a thyrotoxic or familial periodic paralysis channel mutation, we did not identify any previously detected human channel mutation in the hyperthyroid cat presenting hypokalemia. However, based on the small number of affected cats in this study, we cannot yet rule out this molecular mechanism. Notwithstanding, hyperthyroidism should still be considered as a differential diagnosis in hypokalemic feline paralysis.

Thyrotoxic Periodic Paralysis: An Incidental Diagnosis!

“…Inwardly rectifying potassium (Kir) channels mediate the K+ ion current across the cell membrane during repolarization. The Kir channel family is encoded by KCNJ genes [9]. The KCNJ18 gene encodes Kir 2.6, which is one of the seven Kir subfamilies [1][2][9][10].…”

“…The Kir channel family is encoded by KCNJ genes [9]. The KCNJ18 gene encodes Kir 2.6, which is one of the seven Kir subfamilies [1][2][9][10]. KCNJ18-related mutations have been found in up to 33% of the thyrotoxic patients with periodic paralysis [3,11].…”

“…KCNJ18-related mutations have been found in up to 33% of the thyrotoxic patients with periodic paralysis [3,11]. The KCNJ2 (Kir 2.1), and KCNJ12 (Kir 2.2) gene mutations are also associated with TPP [9]. Moreover, increased serum levels of catecholamine and insulin can also blunt the function of Kir channels [2].…”

“…The resulting hypokalemia causes inactivation of voltage-gated sodium channels and finally leads to the paralysis of the motor unit [1]. A few human leukocyte antigen (HLA) genes are prevalent among Asian patients with Graves' disease who developed TPP, but an independent association of HLA genes with TPP has yet to be discovered [9].…”

Absence of 2899C<T Mutation in the WNK4 Gene in a Free-Ranging Lion (Panthera leo) with Polymyopathy

“…In addition, mutations in KCNJ2 have been found associated with non-familial HOKPP, and with thyrotoxic periodic paralysis in humans [18]. Although polymorphisms in these genes have not been found to be associated with hypokalemia in domestic cats [19], their involvement in this polymyopathy syndrome in free-ranging lions cannot be currently be ruled out.…”