<i>KCNG1</i>-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf

Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to characterize the clinicopathologic features of a Belgian Blue x Holstein crossbred calf with paradoxical myotonia congenita, craniofacial d...

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Autores principales:	Joana G. P. Jacinto, Irene M. Häfliger, Eylem Emek Akyürek, Roberta Sacchetto, Cinzia Benazzi, Arcangelo Gentile, Cord Drögemüller
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cattle channelopathy skeletal muscle neuromuscular disorder paradoxical myotonia congenita potassium voltage-gated channel Genetics QH426-470
Acceso en línea:	https://doaj.org/article/fd8e1280d2c1439dbdefea4bd7bec2e4
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spelling	oai:doaj.org-article:fd8e1280d2c1439dbdefea4bd7bec2e42021-11-25T17:42:01Z<i>KCNG1</i>-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf10.3390/genes121117922073-4425https://doaj.org/article/fd8e1280d2c1439dbdefea4bd7bec2e42021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4425/12/11/1792https://doaj.org/toc/2073-4425Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to characterize the clinicopathologic features of a Belgian Blue x Holstein crossbred calf with paradoxical myotonia congenita, craniofacial dysmorphism, and myelodysplasia, and to identify the most likely genetic etiology. The calf displayed episodes of exercise-induced generalized myotonic muscle stiffness accompanied by increase in serum potassium. It also showed slight flattening of the splanchnocranium with deviation to the right side. On gross pathology, myelodysplasia (hydrosyringomielia and segmental hypoplasia) in the lumbosacral intumescence region was noticed. Histopathology of the muscle profile revealed loss of the main shape in 5.3% of muscle fibers. Whole-genome sequencing revealed a heterozygous missense variant in <i>KCNG1</i> affecting an evolutionary conserved residue (p.Trp416Cys). The mutation was predicted to be deleterious and to alter the pore helix of the ion transport domain of the transmembrane protein. The identified variant was present only in the affected calf and not seen in more than 5200 other sequenced bovine genomes. We speculate that the mutation occurred either as a parental germline mutation or post-zygotically in the developing embryo. This study implicates an important role for <i>KCNG1</i> as a member of the potassium voltage-gated channel group in neurodegeneration. Providing the first possible <i>KCNG1</i>-related disease model, we have, therefore, identified a new potential candidate for related conditions both in animals and in humans. This study illustrates the enormous potential of phenotypically well-studied spontaneous mutants in domestic animals to provide new insights into the function of individual genes.Joana G. P. JacintoIrene M. HäfligerEylem Emek AkyürekRoberta SacchettoCinzia BenazziArcangelo GentileCord DrögemüllerMDPI AGarticlecattlechannelopathyskeletal muscleneuromuscular disorderparadoxical myotonia congenitapotassium voltage-gated channelGeneticsQH426-470ENGenes, Vol 12, Iss 1792, p 1792 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cattle channelopathy skeletal muscle neuromuscular disorder paradoxical myotonia congenita potassium voltage-gated channel Genetics QH426-470
spellingShingle	cattle channelopathy skeletal muscle neuromuscular disorder paradoxical myotonia congenita potassium voltage-gated channel Genetics QH426-470 Joana G. P. Jacinto Irene M. Häfliger Eylem Emek Akyürek Roberta Sacchetto Cinzia Benazzi Arcangelo Gentile Cord Drögemüller <i>KCNG1</i>-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf
description	Inherited channelopathies are a clinically and heritably heterogeneous group of disorders that result from ion channel dysfunction. The aim of this study was to characterize the clinicopathologic features of a Belgian Blue x Holstein crossbred calf with paradoxical myotonia congenita, craniofacial dysmorphism, and myelodysplasia, and to identify the most likely genetic etiology. The calf displayed episodes of exercise-induced generalized myotonic muscle stiffness accompanied by increase in serum potassium. It also showed slight flattening of the splanchnocranium with deviation to the right side. On gross pathology, myelodysplasia (hydrosyringomielia and segmental hypoplasia) in the lumbosacral intumescence region was noticed. Histopathology of the muscle profile revealed loss of the main shape in 5.3% of muscle fibers. Whole-genome sequencing revealed a heterozygous missense variant in <i>KCNG1</i> affecting an evolutionary conserved residue (p.Trp416Cys). The mutation was predicted to be deleterious and to alter the pore helix of the ion transport domain of the transmembrane protein. The identified variant was present only in the affected calf and not seen in more than 5200 other sequenced bovine genomes. We speculate that the mutation occurred either as a parental germline mutation or post-zygotically in the developing embryo. This study implicates an important role for <i>KCNG1</i> as a member of the potassium voltage-gated channel group in neurodegeneration. Providing the first possible <i>KCNG1</i>-related disease model, we have, therefore, identified a new potential candidate for related conditions both in animals and in humans. This study illustrates the enormous potential of phenotypically well-studied spontaneous mutants in domestic animals to provide new insights into the function of individual genes.
format	article
author	Joana G. P. Jacinto Irene M. Häfliger Eylem Emek Akyürek Roberta Sacchetto Cinzia Benazzi Arcangelo Gentile Cord Drögemüller
author_facet	Joana G. P. Jacinto Irene M. Häfliger Eylem Emek Akyürek Roberta Sacchetto Cinzia Benazzi Arcangelo Gentile Cord Drögemüller
author_sort	Joana G. P. Jacinto
title	<i>KCNG1</i>-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf
title_short	<i>KCNG1</i>-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf
title_full	<i>KCNG1</i>-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf
title_fullStr	<i>KCNG1</i>-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf
title_full_unstemmed	<i>KCNG1</i>-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf
title_sort	<i>kcng1</i>-related syndromic form of congenital neuromuscular channelopathy in a crossbred calf
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/fd8e1280d2c1439dbdefea4bd7bec2e4
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<i>KCNG1</i>-Related Syndromic Form of Congenital Neuromuscular Channelopathy in a Crossbred Calf

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