RGD Reference Report - A Spontaneous Missense Mutation in Branched Chain Keto Acid Dehydrogenase Kinase in the Rat Affects Both the Central and Peripheral Nervous Systems. - Rat Genome Database

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

Authors: 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 
Citation: Zigler JS, etal., PLoS One. 2016 Jul 29;11(7):e0160447. doi: 10.1371/journal.pone.0160447. eCollection 2016.
RGD ID: 39131293
Pubmed: PMID:27472223   (View Abstract at PubMed)
PMCID: PMC4966912   (View Article at PubMed Central)
DOI: DOI:10.1371/journal.pone.0160447   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
branched-chain keto acid dehydrogenase kinase deficiency  ISOBckdk (Rattus norvegicus)39131293; 39131293DNA:missense mutation:cds:G369E (rat)RGD 
branched-chain keto acid dehydrogenase kinase deficiency  IAGP 39131293DNA:missense mutation:cds:G369E (rat)RGD 
branched-chain keto acid dehydrogenase kinase deficiency  IAGP 39131293compared to NTac:SDRGD 
oligospermia  ISOBckdk (Rattus norvegicus)39131293; 39131293DNA:missense mutation:cds:G369E (rat)RGD 
oligospermia  IAGP 39131293DNA:missense mutation:cds:G369E (rat)RGD 
oligospermia  IAGP 39131293compared to NTac:SDRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
isoleucine catabolic process  IMP 39131293 RGD 
L-leucine catabolic process  IMP 39131293 RGD 
spermatogenesis  IMP 39131293 RGD 
valine catabolic process  IMP 39131293 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
abnormal foot pad morphology  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
abnormal foot pad morphology  IAGP 39131293compared to NTac:SDRGD 
abnormal hindlimb morphology  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
abnormal hindlimb morphology  IAGP 39131293compared to NTac:SDRGD 
abnormal Schwann cell morphology  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
abnormal sciatic nerve morphology  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
abnormal soleus morphology  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
abnormal soleus morphology  IAGP 39131293compared to NTac:SDRGD 
decreased body size  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
decreased body size  IAGP 39131293compared to NTac:SDRGD 
decreased brain weight  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
decreased brain weight  IAGP 39131293compared to NTac:SDRGD 
decreased circulating isoleucine level  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
decreased circulating isoleucine level  IAGP 39131293compared to NTac:SDRGD 
decreased circulating leucine level  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
decreased circulating leucine level  IAGP 39131293compared to NTac:SDRGD 
decreased circulating valine level  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
decreased circulating valine level  IAGP 39131293compared to NTac:SDRGD 
enlarged lateral ventricles  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
enlarged lateral ventricles  IAGP 39131293compared to NTac:SDRGD 
long toenails  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
long toenails  IAGP 39131293compared to NTac:SDRGD 
reduced male fertility  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
reduced male fertility  IAGP 39131293compared to NTac:SDRGD 
testis hypoplasia  IAGP 39131293DNA:missense mutation:cds:G369E ratRGD 
testis hypoplasia  IAGP 39131293compared to NTac:SDRGD 
Objects Annotated

Genes (Rattus norvegicus)
Bckdk  (branched chain ketoacid dehydrogenase kinase)

Genes (Mus musculus)
Bckdk  (branched chain ketoacid dehydrogenase kinase)

Genes (Homo sapiens)
BCKDK  (branched chain keto acid dehydrogenase kinase)

Strains
SD-Bckdkm1Dbsa  (NA)


Additional Information