Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency

Uematsu, Mitsugu; Sakamoto, Osamu; Sato, Noriko; Kumagai, Naoya; Morimoto, Takeshi; Yamaguchi, Seiji; Hasegawa, Yuki; Kobayashi, Hironori; Ihara, Kenji; Yoshino, Makoto; Watanabe, Yoriko; Isobe, Takashi; Yokoyama, Takato; Kiwaki, Kohji; Nakamura, Kimitoshi; Endo, Fumio; Tsuchiya, Shigeru; Ohura, Toshihiro

doi:10.1007/s10038-007-0211-9

Cited by 17 publications

(13 citation statements)

References 13 publications

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“…A total of six MCCC2 mutations were identified in the 17 out of 18 alleles (94.4%) from the nine unrelated Korean families, which were all missense mutations (Table 1). Of note, c.838G4T (p.D280Y), a previously reported mutation in a Japanese patient with MCG by Uematsu et al, 14 was the most common mutation in our patients. p.D280Y was identified in the 12/18 alleles (66.7%), indicating a founder effect.…”

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confidence: 55%

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Uneventful clinical courses of Korean patients with methylcrotonylglycinuria and their common mutations

et al. 2011

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Methylcrotonylglycinuria (MCG) is an inborn error of leucine catabolism and results from the deficiency of 3-methylcrotonyl-CoA carboxylase. Patients with MCG show a highly variable clinical phenotype, ranging from asymptomatic to severe. With the introduction of newborn screening using tandem mass spectrometry, most patients with MCG are identified in their asymptomatic neonatal periods. Owing to their fair clinical outcomes, there exists a controversy over the need for aggressive medical intervention or even for newborn screening for MCG. Our study, reporting 11 Korean MCG patients from nine unrelated families, who were identified by newborn screening or family member testing and normally developed without experiencing an metabolic crisis during the follow-up period of 2.6±1.96 years (range, 1-10 years), indicates that the aggressive medical intervention might not be needed at least for the MCG patients identified by screening program in asymptomatic period. A total of six MCCC2 mutations, but no MCCC1 mutation, were identified in 17 of 18 alleles (94.4%). p.D280Y was identified in the 12/18 alleles (66.7%), indicating a founder effect. Moreover, the rest five variants, p.S342K, p.Q496H, p.P552S, p.T556A and p.P459S, were all previously unreported. The results of our study indicate that the distinct molecular genetic characteristics exist in Korean MCG patients.

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confidence: 55%

“…p.D280Y was identified in the 12/18 alleles (66.7%), indicating a founder effect. In the report by Uematsu et al, 14 this variant was only found in 1/6 alleles (16.7%). Currently, it is unknown whether p.D280Y is the common mutation in other East-Asian countries including Japan and China, as in Korea.…”

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confidence: 83%

Uneventful clinical courses of Korean patients with methylcrotonylglycinuria and their common mutations

et al. 2011

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“…Some patients develop an acute metabolic crisis usually triggered by intercurrent infections or introduction of a protein-rich diet in early childhood. Symptoms include vomiting, opisthotonus, involuntary movements, seizures, coma and apnoea typically associated with metabolic acidosis, hypoglycemia and in some cases mild hyperammonemia [3,7,23-27]. Others present with neurological abnormalities such as seizures, muscular hypotonia or developmental delay [6,18,28-31].…”

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confidence: 99%

3-methylcrotonyl-CoA carboxylase deficiency: Clinical, biochemical, enzymatic and molecular studies in 88 individuals

Grünert

Stucki

Morscher

et al. 2012

Orphanet J Rare Dis

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BackgroundIsolated 3-methylcrotonyl-CoA carboxylase (MCC) deficiency is an autosomal recessive disorder of leucine metabolism caused by mutations in MCCC1 or MCCC2 encoding the α and β subunit of MCC, respectively. The phenotype is highly variable ranging from acute neonatal onset with fatal outcome to asymptomatic adults.MethodsWe report clinical, biochemical, enzymatic and mutation data of 88 MCC deficient individuals, 53 identified by newborn screening, 26 diagnosed due to clinical symptoms or positive family history and 9 mothers, identified following the positive newborn screening result of their baby.ResultsFifty-seven percent of patients were asymptomatic while 43% showed clinical symptoms, many of which were probably not related to MCC deficiency but due to ascertainment bias. However, 12 patients (5 of 53 identified by newborn screening) presented with acute metabolic decompensations. We identified 15 novel MCCC1 and 16 novel MCCC2 mutant alleles. Additionally, we report expression studies on 3 MCCC1 and 8 MCCC2 mutations and show an overview of all 132 MCCC1 and MCCC2 variants known to date.ConclusionsOur data confirm that MCC deficiency, despite low penetrance, may lead to a severe clinical phenotype resembling classical organic acidurias. However, neither the genotype nor the biochemical phenotype is helpful in predicting the clinical course.

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“…The structure of PaMCC provides a foundation for understanding the molecular basis of its disease-causing mutations in HsMCC, which represent one of the most frequently observed inborn errors of metabolism 1–4,19–21 . The missense mutations are distributed throughout the holoenzyme (Fig.…”

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An unanticipated architecture of the 750-kDa α6β6 holoenzyme of 3-methylcrotonyl-CoA carboxylase

Huang

Zhou

et al. 2011

Nature

114

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3-methylcrotonyl-CoA carboxylase (MCC), a member of the biotin-dependent carboxylase superfamily, is essential for the metabolism of leucine, and deficient mutations in this enzyme are linked to methylcrotonylglycinuria (MCG) and other serious diseases in humans 1–8. MCC has strong sequence conservation with propionyl-CoA carboxylase (PCC), and their holoenzymes are both 750 kD α6β6 dodecamers. Therefore the architecture of the MCC holoenzyme is expected to be highly similar to that of PCC 9. Here we report the crystal structures of the Pseudomonas aeruginosa MCC (PaMCC) holoenzyme, alone and in complex with coenzyme A. Surprisingly, the structures show that the architecture and overall shape of PaMCC are strikingly different when compared to PCC. The α subunits display trimeric association in the PaMCC holoenzyme while they have no contacts with each other in PCC. Moreover, the positions of the two domains in the β subunit in PaMCC are swapped relative to those in PCC. The structural information establishes a foundation for understanding the disease-causing mutations of MCC and provides new insights into the catalytic mechanism and evolution of biotin-dependent carboxylases. The large structural differences between MCC and PCC also have general implications for the relationship between sequence conservation and structural similarity.

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Novel mutations in five Japanese patients with 3-methylcrotonyl-CoA carboxylase deficiency

Cited by 17 publications

References 13 publications

Uneventful clinical courses of Korean patients with methylcrotonylglycinuria and their common mutations

Uneventful clinical courses of Korean patients with methylcrotonylglycinuria and their common mutations

3-methylcrotonyl-CoA carboxylase deficiency: Clinical, biochemical, enzymatic and molecular studies in 88 individuals

An unanticipated architecture of the 750-kDa α6β6 holoenzyme of 3-methylcrotonyl-CoA carboxylase

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