A Spontaneous Missense Mutation in Branched Chain Keto Acid Dehydrogenase Kinase in the Rat Affects Both the Central and Peripheral Nervous Systems

J. Samuel Zigler, Colin A. Hodgkinson, Megan Wright, Andrew Klise, Olof Sundin, Karl W. Broman, Fielding Hejtmancik, Hao Huang, Bonnie Patek, Yuri Sergeev, Stacey Hose, Cory Brayton, Jiao Xaiodong, David Vasquez, Nicholas Maragakis, Susumu Mori, David Goldman, Ahmet Hoke, Debasish Sinha

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

A novel mutation, causing a phenotype we named frogleg because its most obvious characteristic is a severe splaying of the hind limbs, arose spontaneously in a colony of Sprague-Dawley rats. Frogleg is a complex phenotype that includes abnormalities in hind limb function, reduced brain weight with dilated ventricles and infertility. Using micro-satellite markers spanning the entire rat genome, the mutation was mapped to a region of rat chromosome 1 between D1Rat131 and D1Rat287. Analysis of whole genome sequencing data within the linkage interval, identified a missense mutation in the branched-chain alpha-keto dehydrogenase kinase (Bckdk) gene. The protein encoded by Bckdk is an integral part of an enzyme complex located in the mitochondrial matrix of many tissues which regulates the levels of the branched-chain amino acids (BCAAs), leucine, isoleucine and valine. BCAAs are essential amino acids (not synthesized by the body), and circulating levels must be tightly regulated; levels that are too high or too low are both deleterious. BCKDK phosphorylates Ser293 of the E1α subunit of the BCKDH protein, which catalyzes the rate-limiting step in the catabolism of the BCAAs, inhibiting BCKDH and thereby, limiting breakdown of the BCAAs. In contrast, when Ser293 is not phosphorylated, BCKDH activity is unchecked and the levels of the BCAAs will decrease dramatically. The mutation is located within the kinase domain of Bckdk and is predicted to be damaging. Consistent with this, we show that in rats homozygous for the mutation, phosphorylation of BCKDH in the brain is markedly decreased relative to wild type or heterozygous littermates. Further, circulating levels of the BCAAs are reduced by 70-80% in animals homozygous for the mutation. The frogleg phenotype shares important characteristics with a previously described Bckdk knockout mouse and with human subjects with Bckdk mutations. In addition, we report novel data regarding peripheral neuropathy of the hind limbs.

Original languageEnglish (US)
Pages (from-to)e0160447
JournalPLoS One
Volume11
Issue number7
DOIs
StatePublished - 2016

Fingerprint

3-methyl-2-oxobutanoate dehydrogenase (lipoamide)
3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)
Branched Chain Amino Acids
peripheral nervous system
missense mutation
branched chain amino acids
Peripheral Nervous System
Neurology
Missense Mutation
central nervous system
Rats
phosphotransferases (kinases)
Phosphotransferases
Central Nervous System
Oxidoreductases
mutation
Mutation
rats
limbs (animal)
Extremities

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

A Spontaneous Missense Mutation in Branched Chain Keto Acid Dehydrogenase Kinase in the Rat Affects Both the Central and Peripheral Nervous Systems. / Zigler, J. Samuel; Hodgkinson, Colin A.; Wright, Megan; Klise, Andrew; Sundin, Olof; Broman, Karl W.; Hejtmancik, Fielding; Huang, Hao; Patek, Bonnie; Sergeev, Yuri; Hose, Stacey; Brayton, Cory; Xaiodong, Jiao; Vasquez, David; Maragakis, Nicholas; Mori, Susumu; Goldman, David; Hoke, Ahmet; Sinha, Debasish.

In: PLoS One, Vol. 11, No. 7, 2016, p. e0160447.

Research output: Contribution to journalArticle

Zigler, JS, Hodgkinson, CA, Wright, M, Klise, A, Sundin, O, Broman, KW, Hejtmancik, F, Huang, H, Patek, B, Sergeev, Y, Hose, S, Brayton, C, Xaiodong, J, Vasquez, D, Maragakis, N, Mori, S, Goldman, D, Hoke, A & Sinha, D 2016, 'A Spontaneous Missense Mutation in Branched Chain Keto Acid Dehydrogenase Kinase in the Rat Affects Both the Central and Peripheral Nervous Systems', PLoS One, vol. 11, no. 7, pp. e0160447. https://doi.org/10.1371/journal.pone.0160447
Zigler, J. Samuel ; Hodgkinson, Colin A. ; Wright, Megan ; Klise, Andrew ; Sundin, Olof ; Broman, Karl W. ; Hejtmancik, Fielding ; Huang, Hao ; Patek, Bonnie ; Sergeev, Yuri ; Hose, Stacey ; Brayton, Cory ; Xaiodong, Jiao ; Vasquez, David ; Maragakis, Nicholas ; Mori, Susumu ; Goldman, David ; Hoke, Ahmet ; Sinha, Debasish. / A Spontaneous Missense Mutation in Branched Chain Keto Acid Dehydrogenase Kinase in the Rat Affects Both the Central and Peripheral Nervous Systems. In: PLoS One. 2016 ; Vol. 11, No. 7. pp. e0160447.
@article{0bb5b325c86a4508af3df2a1f973ce60,
title = "A Spontaneous Missense Mutation in Branched Chain Keto Acid Dehydrogenase Kinase in the Rat Affects Both the Central and Peripheral Nervous Systems",
abstract = "A novel mutation, causing a phenotype we named frogleg because its most obvious characteristic is a severe splaying of the hind limbs, arose spontaneously in a colony of Sprague-Dawley rats. Frogleg is a complex phenotype that includes abnormalities in hind limb function, reduced brain weight with dilated ventricles and infertility. Using micro-satellite markers spanning the entire rat genome, the mutation was mapped to a region of rat chromosome 1 between D1Rat131 and D1Rat287. Analysis of whole genome sequencing data within the linkage interval, identified a missense mutation in the branched-chain alpha-keto dehydrogenase kinase (Bckdk) gene. The protein encoded by Bckdk is an integral part of an enzyme complex located in the mitochondrial matrix of many tissues which regulates the levels of the branched-chain amino acids (BCAAs), leucine, isoleucine and valine. BCAAs are essential amino acids (not synthesized by the body), and circulating levels must be tightly regulated; levels that are too high or too low are both deleterious. BCKDK phosphorylates Ser293 of the E1α subunit of the BCKDH protein, which catalyzes the rate-limiting step in the catabolism of the BCAAs, inhibiting BCKDH and thereby, limiting breakdown of the BCAAs. In contrast, when Ser293 is not phosphorylated, BCKDH activity is unchecked and the levels of the BCAAs will decrease dramatically. The mutation is located within the kinase domain of Bckdk and is predicted to be damaging. Consistent with this, we show that in rats homozygous for the mutation, phosphorylation of BCKDH in the brain is markedly decreased relative to wild type or heterozygous littermates. Further, circulating levels of the BCAAs are reduced by 70-80{\%} in animals homozygous for the mutation. The frogleg phenotype shares important characteristics with a previously described Bckdk knockout mouse and with human subjects with Bckdk mutations. In addition, we report novel data regarding peripheral neuropathy of the hind limbs.",
author = "Zigler, {J. Samuel} and Hodgkinson, {Colin A.} and Megan Wright and Andrew Klise and Olof Sundin and Broman, {Karl W.} and Fielding Hejtmancik and Hao Huang and Bonnie Patek and Yuri Sergeev and Stacey Hose and Cory Brayton and Jiao Xaiodong and David Vasquez and Nicholas Maragakis and Susumu Mori and David Goldman and Ahmet Hoke and Debasish Sinha",
year = "2016",
doi = "10.1371/journal.pone.0160447",
language = "English (US)",
volume = "11",
pages = "e0160447",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "7",

}

TY - JOUR

T1 - A Spontaneous Missense Mutation in Branched Chain Keto Acid Dehydrogenase Kinase in the Rat Affects Both the Central and Peripheral Nervous Systems

AU - Zigler, J. Samuel

AU - Hodgkinson, Colin A.

AU - Wright, Megan

AU - Klise, Andrew

AU - Sundin, Olof

AU - Broman, Karl W.

AU - Hejtmancik, Fielding

AU - Huang, Hao

AU - Patek, Bonnie

AU - Sergeev, Yuri

AU - Hose, Stacey

AU - Brayton, Cory

AU - Xaiodong, Jiao

AU - Vasquez, David

AU - Maragakis, Nicholas

AU - Mori, Susumu

AU - Goldman, David

AU - Hoke, Ahmet

AU - Sinha, Debasish

PY - 2016

Y1 - 2016

N2 - A novel mutation, causing a phenotype we named frogleg because its most obvious characteristic is a severe splaying of the hind limbs, arose spontaneously in a colony of Sprague-Dawley rats. Frogleg is a complex phenotype that includes abnormalities in hind limb function, reduced brain weight with dilated ventricles and infertility. Using micro-satellite markers spanning the entire rat genome, the mutation was mapped to a region of rat chromosome 1 between D1Rat131 and D1Rat287. Analysis of whole genome sequencing data within the linkage interval, identified a missense mutation in the branched-chain alpha-keto dehydrogenase kinase (Bckdk) gene. The protein encoded by Bckdk is an integral part of an enzyme complex located in the mitochondrial matrix of many tissues which regulates the levels of the branched-chain amino acids (BCAAs), leucine, isoleucine and valine. BCAAs are essential amino acids (not synthesized by the body), and circulating levels must be tightly regulated; levels that are too high or too low are both deleterious. BCKDK phosphorylates Ser293 of the E1α subunit of the BCKDH protein, which catalyzes the rate-limiting step in the catabolism of the BCAAs, inhibiting BCKDH and thereby, limiting breakdown of the BCAAs. In contrast, when Ser293 is not phosphorylated, BCKDH activity is unchecked and the levels of the BCAAs will decrease dramatically. The mutation is located within the kinase domain of Bckdk and is predicted to be damaging. Consistent with this, we show that in rats homozygous for the mutation, phosphorylation of BCKDH in the brain is markedly decreased relative to wild type or heterozygous littermates. Further, circulating levels of the BCAAs are reduced by 70-80% in animals homozygous for the mutation. The frogleg phenotype shares important characteristics with a previously described Bckdk knockout mouse and with human subjects with Bckdk mutations. In addition, we report novel data regarding peripheral neuropathy of the hind limbs.

AB - A novel mutation, causing a phenotype we named frogleg because its most obvious characteristic is a severe splaying of the hind limbs, arose spontaneously in a colony of Sprague-Dawley rats. Frogleg is a complex phenotype that includes abnormalities in hind limb function, reduced brain weight with dilated ventricles and infertility. Using micro-satellite markers spanning the entire rat genome, the mutation was mapped to a region of rat chromosome 1 between D1Rat131 and D1Rat287. Analysis of whole genome sequencing data within the linkage interval, identified a missense mutation in the branched-chain alpha-keto dehydrogenase kinase (Bckdk) gene. The protein encoded by Bckdk is an integral part of an enzyme complex located in the mitochondrial matrix of many tissues which regulates the levels of the branched-chain amino acids (BCAAs), leucine, isoleucine and valine. BCAAs are essential amino acids (not synthesized by the body), and circulating levels must be tightly regulated; levels that are too high or too low are both deleterious. BCKDK phosphorylates Ser293 of the E1α subunit of the BCKDH protein, which catalyzes the rate-limiting step in the catabolism of the BCAAs, inhibiting BCKDH and thereby, limiting breakdown of the BCAAs. In contrast, when Ser293 is not phosphorylated, BCKDH activity is unchecked and the levels of the BCAAs will decrease dramatically. The mutation is located within the kinase domain of Bckdk and is predicted to be damaging. Consistent with this, we show that in rats homozygous for the mutation, phosphorylation of BCKDH in the brain is markedly decreased relative to wild type or heterozygous littermates. Further, circulating levels of the BCAAs are reduced by 70-80% in animals homozygous for the mutation. The frogleg phenotype shares important characteristics with a previously described Bckdk knockout mouse and with human subjects with Bckdk mutations. In addition, we report novel data regarding peripheral neuropathy of the hind limbs.

UR - http://www.scopus.com/inward/record.url?scp=85027279460&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85027279460&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0160447

DO - 10.1371/journal.pone.0160447

M3 - Article

C2 - 27472223

AN - SCOPUS:85027279460

VL - 11

SP - e0160447

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 7

ER -