MCCC mutants don't synthesize beta-methylglutaconyl-CoA

Stable Identifier
R-HSA-9909466
Type
Reaction [transition]
Species
Homo sapiens
Compartment
mitochondrial matrix
ReviewStatus
5/5
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MCCC mutants don't synthesize beta-methylglutaconyl-CoA
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The following mutations in MCCC1 have been identified in patients with MCCC deficiency I. They have been shown to have compromised activity in vitro and are classified as either "likely pathological" or "pathological" in ClinVar despite variable clinical presentations:
M325R: appears to abolish the ability of the protein to be biotinylated, possibly affecting protein stability (Gallardo et al, 2001).

R385S: appears to affect protein activity without affecting stability. May act as a dominant negative (Steen et al, 1999; Gallardo et al, 2001; Baumgartner et al, 2001; Baumgartner et al, 2004; Fonseca et al, 2016; Dantas et al, 2005; Morscher et al, 2012).

L437P: abolishes enzyme activity (Baumgartner et al, 2001)

I460M: reduces enzyme activity to <1% (Murayama et al, 1997; Uematsu et al, 2007)

D532H: This mutation arises as a result of a nucleotide change causing an alteration of a splice site, and results in a truncated protein (Baumgartner et al, 2001)

V694*: This mutation leads to premature truncation and removes the essential biotinylation site (Holzinger et al, 2001)


The following mutations in MCCC2 have been identified in patients with MCCC deficiency II, have been shown to have compromised activity in vitro and are classified as either "likely pathological" or "pathological" in ClinVar, despite variable clinical presentations:

E99Q: this mutation shows no detectable MCCC activity in expression studies and variable clinical outcome (Baumgartner et al, 2001; Grünert et al, 2012).

S173L: no detectable MCCC activity in expression studies (Baumgartner et al, 2001).

H190Y: mutation of a highly conserved residue, severely decreased MCCC activity (Dantas et al, 2005)

V339M: ~4% residual MCCC activity with severe clinical outcome in two Turkish patients (Baumgartner et al, 2001).

G352R: mutation of a highly conserved residue, severely decreased MCCC activity (Dantas et al, 2005; Grünert et al, 2012)

A456V: mutation of a highly conserved residue, virtually no detectable MCCC activity (Dantas et al, 2005; Grünert et al, 2012).
Literature References
PubMed ID Title Journal Year
17968484 Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency

Uematsu, M, Sakamoto, O, Sugawara, N, Kumagai, N, Morimoto, T, Yamaguchi, S, Hasegawa, Y, Kobayashi, H, Ihara, K, Yoshino, M, Watanabe, Y, Inokuchi, T, Yokoyama, T, Kiwaki, K, Nakamura, K, Endo, F, Tsuchiya, S, Ohura, T

J Hum Genet 2007
11406611 Cloning of the human MCCA and MCCB genes and mutations therein reveal the molecular cause of 3-methylcrotonyl-CoA: carboxylase deficiency.

Holzinger, A, Röschinger, W, Lagler, F, Mayerhofer, PU, Lichtner, P, Kattenfeld, T, Thuy, LP, Nyhan, WL, Koch, HG, Muntau, AC, Roscher, AA

Hum Mol Genet 2001
15359379 Isolated 3-methylcrotonyl-CoA carboxylase deficiency: evidence for an allele-specific dominant negative effect and responsiveness to biotin therapy

Baumgartner, MR, Dantas, MF, Suormala, T, Almashanu, S, Giunta, C, Friebel, D, Gebhardt, B, Fowler, B, Hoffmann, GF, Baumgartner, ER, Valle, D

Am J Hum Genet 2004
16010683 3-Methylcrotonyl-CoA carboxylase deficiency: mutation analysis in 28 probands, 9 symptomatic and 19 detected by newborn screening

Dantas, MF, Suormala, T, Randolph, A, Coelho, D, Fowler, B, Valle, D, Baumgartner, MR

Hum Mutat 2005
9187484 Isolated 3-methylcrotonyl-CoA carboxylase deficiency in a 15-year-old girl

Murayama, K, Kimura, M, Yamaguchi, S, Shinka, T, Kodama, K

Brain Dev 1997
11181649 The molecular basis of human 3-methylcrotonyl-CoA carboxylase deficiency.

Baumgartner, MR, Almashanu, S, Suormala, T, Obie, C, Cole, RN, Packman, S, Baumgartner, ER, Valle, D

J Clin Invest 2001
22642865 3-methylcrotonyl-CoA carboxylase deficiency: clinical, biochemical, enzymatic and molecular studies in 88 individuals

Grünert, SC, Stucki, M, Morscher, RJ, Suormala, T, Bürer, C, Burda, P, Christensen, E, Ficicioglu, C, Herwig, J, Kölker, S, Möslinger, D, Pasquini, E, Santer, R, Schwab, KO, Wilcken, B, Fowler, B, Yue, WW, Baumgartner, MR

Orphanet J Rare Dis 2012
11170888 The molecular basis of 3-methylcrotonylglycinuria, a disorder of leucine catabolism

Gallardo, ME, Desviat, LR, Rodríguez, JM, Esparza-Gordillo, J, Pérez-Cerdá, C, Pérez, B, Rodríguez-Pombo, P, Criado, O, Sanz, R, Morton, DH, Gibson, KM, Le, TP, Ribes, A, de Córdoba, SR, Ugarte, M, Peñalva, MA

Am J Hum Genet 2001
10485305 Metabolic stroke in isolated 3-methylcrotonyl-CoA carboxylase deficiency

Steen, C, Baumgartner, ER, Duran, M, Lehnert, W, Suormala, T, Fingerhut, R, Stehn, M, Kohlschutter, A

Eur J Pediatr 1999
27601257 3-Methylcrotonyl-CoA carboxylase deficiency: Mutational spectrum derived from comprehensive newborn screening

Fonseca, H, Azevedo, L, Serrano, C, Sousa, C, Marcão, A, Vilarinho, L

Gene 2016
22264772 A single mutation in MCCC1 or MCCC2 as a potential cause of positive screening for 3-methylcrotonyl-CoA carboxylase deficiency

Morscher, RJ, Grünert, SC, Bürer, C, Burda, P, Suormala, T, Fowler, B, Baumgartner, MR

Mol Genet Metab 2012
Participants
Input
Participates
as an event of
Catalyst Activity

methylcrotonoyl-CoA carboxylase activity of MCCC mutant complexes [mitochondrial matrix]

Physical Entity
MCCC mutant complexes [mitochondrial matrix] (Homo sapiens)
Activity
methylcrotonoyl-CoA carboxylase activity (GO:0004485)
Normal reaction
beta-methylcrotonyl-CoA + ATP + HCO3- <=> beta-methylglutaconyl-CoA + ADP + orthophosphate + H2O (MCCA) (Homo sapiens)
Functional status

Loss of function of MCCC mutant complexes [mitochondrial matrix]

Normal Entity
Disease Entity
Status
Disease
Name Identifier Synonyms
3-methylcrotonyl-CoA carboxylase deficiency DOID:0050710 3MCC deficiency, BMCC deficiency, 3-Methylcrotonylglycinuria
3-Methylcrotonyl-CoA carboxylase 1 deficiency DOID:0080579
Cross References
Mondo
Authored
Rothfels, K  (2024-07-29)
Reviewed
D'Eustachio, P  (2024-08-18)
Created
Rothfels, K  (2024-05-13)
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