Incidental Mutation 'P0014:Gcdh'

• ID: 7605
• Institutional Source: Beutler Lab
• Gene Symbol: Gcdh
• Ensembl Gene: ENSMUSG00000003809
• Gene Name: glutaryl-Coenzyme A dehydrogenase
• Synonyms: D17825
• MMRRC Submission: 038267-MU
• Essential gene?: Non essential (E-score: 0.000)
• Stock #: P0014 (G1)
• Status: Validated
• Chromosome: 8
• Chromosomal Location: 85613022-85620550 bp(-) (GRCm39)
• Type of Mutation: critical splice donor site (2 bp from exon)
• DNA Base Change (assembly): A to G at 85615154 bp (GRCm39)
• Zygosity: Heterozygous
• Ref Sequence: ENSEMBL: ENSMUSP00000105367
• Gene Model: predicted gene model for transcript(s): [ENSMUST00000003907] [ENSMUST00000003922] [ENSMUST00000109745] [ENSMUST00000136026] [ENSMUST00000142748] [ENSMUST00000170296]
• AlphaFold: Q60759
• Predicted Effect: probably null; Transcript: ENSMUST00000003907
• SMART Domains: Protein: ENSMUSP00000003907; Gene: ENSMUSG00000003809

Domain	Start	End	E-Value	Type
low complexity region	2	24	N/A	INTRINSIC
Pfam:Acyl-CoA_dh_N	61	172	1.5e-29	PFAM
Pfam:Acyl-CoA_dh_M	176	269	3.8e-22	PFAM
Pfam:Acyl-CoA_dh_1	287	429	2.9e-30	PFAM
Pfam:Acyl-CoA_dh_2	295	418	3.6e-9	PFAM

• Predicted Effect: probably benign; Transcript: ENSMUST00000003922
• Predicted Effect: probably null; Transcript: ENSMUST00000109745
• SMART Domains: Protein: ENSMUSP00000105367; Gene: ENSMUSG00000003809

Domain	Start	End	E-Value	Type
low complexity region	2	24	N/A	INTRINSIC
Pfam:Acyl-CoA_dh_N	61	172	8.2e-28	PFAM
Pfam:Acyl-CoA_dh_M	176	230	2.2e-21	PFAM
low complexity region	269	280	N/A	INTRINSIC
Pfam:Acyl-CoA_dh_1	287	429	2.6e-30	PFAM
Pfam:Acyl-CoA_dh_2	295	418	2.1e-11	PFAM

• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000128023
• Predicted Effect: probably benign; Transcript: ENSMUST00000136026
• SMART Domains: Protein: ENSMUSP00000122159; Gene: ENSMUSG00000003824

Domain	Start	End	E-Value	Type
coiled coil region	52	83	N/A	INTRINSIC

• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000136462
• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000139180
• Predicted Effect: noncoding transcript; Transcript: ENSMUST00000144466
• Predicted Effect: probably benign; Transcript: ENSMUST00000142748
• SMART Domains: Protein: ENSMUSP00000116584; Gene: ENSMUSG00000003809

Domain	Start	End	E-Value	Type
low complexity region	2	24	N/A	INTRINSIC
PDB:2R0M|A	45	66	5e-6	PDB

• Predicted Effect: probably benign; Transcript: ENSMUST00000170296
• SMART Domains: Protein: ENSMUSP00000131438; Gene: ENSMUSG00000003824

Domain	Start	End	E-Value	Type
coiled coil region	58	89	N/A	INTRINSIC

• Meta Mutation Damage Score: 0.9494
• Coding Region Coverage:
  • 1x: 85.4%
  • 3x: 80.7%
  • 10x: 66.7%
  • 20x: 50.4%
• Validation Efficiency: 95% (100/105)
• MGI Phenotype: FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] The protein encoded by this gene belongs to the acyl-CoA dehydrogenase family. It catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. The enzyme exists in the mitochondrial matrix as a homotetramer of 45-kD subunits. Mutations in this gene result in the metabolic disorder glutaric aciduria type 1, which is also known as glutaric acidemia type I. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 12. [provided by RefSeq, Mar 2013] ; PHENOTYPE: Homozygotes for a targeted null mutation exhibit a mild motor deficit associated with a diffuse spongiform myelinopathy and elevated levels of glutaric acid and 3-hydroxyglutaric acid. [provided by MGI curators]
• Allele List at MGI:

  All alleles(1) : Targeted(1)

• Posted On: 2012-10-05
• Science Writer: Anne Murray

Protein Function and Prediction

Glutaryl-CoA dehydrogenase (Gcdh) is an acyl dehydrogenase involved in the metabolism of lysine, hydroxylysine, and tryptophan (OMIM *608801).

Expression/Localization

Gcdh is a homotetramer in the mitochondrial matrix (1).  In the mouse brain, Gcdh is restricted to neurons (2).

Background

Mutations in GCDH can cause glutaricaciduria, type I (OMIM #231670), an autosomal recessive metabolic disorder characterized by gliosis and neuronal loss in the basal ganglia and a progressive movement disorder that usually begins during the first year of life (3;4).  Patients have increased concentrations of glutaric acid (GA), 3-hydroxyglutaric acid (3HGA), glutaconic acid and glutarylcarnitine in the body fluids and tissues.

Gcdh^{tm1Dmk/tm1Dmk}; MGI: 2182942

involves: 129S4/SvJae * C57BL/6J

Homozygous animals have difficulty righting themselves when placed on their backs and impaired motor coordination (5).  These mice also have elevated glutaric acid levels and elevated 3-OH gluatric acid levels in the urine, enlarged kidney, and spongiform myelinopathy (5).

Gcdh-deficient mice have an age-dependent susceptibility to encephalopathy; weaned mice have neuronal damage after exposure to dietary protein with enlarged mitochondria and neurofilament disorganization (2).  Limiting brain lysine uptake and decreasing brain lysine catabolism increased survival and decreased injury to the brain (2).

Gcdh^{tm1Dmk/tm1Dmk}; MGI: 2182942

129SvEv background

Creatinine kinase activity is inhibited in brain and skeletal muscle of lysine-treated mice; Na⁺, K⁺-ATPase activity was also inhibited in the brain (6).  There are no significant changes in creatinine kinase and Na⁺, K⁺-ATPase activity in homozygous animals fed with normal chow (6).  Na⁺, K⁺-ATPase activity and expression in the cerebral cortex of homozygous animals was observed (7).

References

  1. Lenich, A. C., and Goodman, S. I. (1986) The Purification and Characterization of Glutaryl-Coenzyme A Dehydrogenase from Porcine and Human Liver. J Biol Chem. 261, 4090-4096.

  2. Zinnanti, W. J., Lazovic, J., Housman, C., LaNoue, K., O'Callaghan, J. P., Simpson, I., Woontner, M., Goodman, S. I., Connor, J. R., Jacobs, R. E., and Cheng, K. C. (2007) Mechanism of Age-Dependent Susceptibility and Novel Treatment Strategy in Glutaric Acidemia Type I. J Clin Invest. 117, 3258-3270.

  3. Goodman, S. I., Kratz, L. E., DiGiulio, K. A., Biery, B. J., Goodman, K. E., Isaya, G., and Frerman, F. E. (1995) Cloning of Glutaryl-CoA Dehydrogenase cDNA, and Expression of Wild Type and Mutant Enzymes in Escherichia Coli. Hum Mol Genet. 4, 1493-1498.

  4. Biery, B. J., Stein, D. E., Morton, D. H., and Goodman, S. I. (1996) Gene Structure and Mutations of Glutaryl-Coenzyme A Dehydrogenase: Impaired Association of Enzyme Subunits that is due to an A421V Substitution Causes Glutaric Acidemia Type I in the Amish. Am J Hum Genet. 59, 1006-1011.

  5. Koeller, D. M., Woontner, M., Crnic, L. S., Kleinschmidt-DeMasters, B., Stephens, J., Hunt, E. L., and Goodman, S. I. (2002) Biochemical, Pathologic and Behavioral Analysis of a Mouse Model of Glutaric Acidemia Type I. Hum Mol Genet. 11, 347-357.

  6. Amaral, A. U., Cecatto, C., Seminotti, B., Zanatta, A., Fernandes, C. G., Busanello, E. N., Braga, L. M., Ribeiro, C. A., de Souza, D. O., Woontner, M., Koeller, D. M., Goodman, S., and Wajner, M. (2012) Marked Reduction of Na(+), K(+)-ATPase and Creatine Kinase Activities Induced by Acute Lysine Administration in Glutaryl-CoA Dehydrogenase Deficient Mice. Mol Genet Metab. 107, 81-86.

  7. Amaral, A. U., Seminotti, B., Cecatto, C., Fernandes, C. G., Busanello, E. N., Zanatta, A., Kist, L. W., Bogo, M. R., de Souza, D. O., Woontner, M., Goodman, S., Koeller, D. M., and Wajner, M. (2012) Reduction of Na(+), K(+)-ATPase Activity and Expression in Cerebral Cortex of Glutaryl-CoA Dehydrogenase Deficient Mice: A Possible Mechanism for Brain Injury in Glutaric Aciduria Type I. Mol Genet Metab. 107, 375-382.