Gene Preference in Maple Syrup Urine Disease

Nellis, Mary M.; Danner, Dean J.

doi:10.1086/316950

Cited by 65 publications

(49 citation statements)

References 18 publications

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“…Somatic cell complementation studies applied to the cell strains allowed their classification into the genetic subtypes Ia, Ib and II according to the gene presumable harboring the mutant alleles. The distribution observed, 15 /33 in the Ib subtype, 10 /33 in the Ia, 7/ 33 in the II and 1 with an ambiguous result is similar to that found in other studied populations (Henneke, et al, 2003;Nellis and Danner, 2001). No EIII genetic subtype strain has been detected in this cohort (data not shown).…”

Section: Resultssupporting

confidence: 86%

Mutational spectrum of maple syrup urine disease in Spain

et al. 2006

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Mutations in any of the three different genes BCKDHA, BCKDHB, and DBT encoding for the E1alpha, E1beta, and E2 catalytic components of the branched-chain alpha-ketoacid dehydrogenase (BCKD) complex can cause maple syrup urine disease (MSUD). The disease presents heterogeneous clinical and molecular phenotypes. Severity of the disease ranges from the classical to the mildest variant types. Here, we describe the MSUD genotypes and related phenotypes in a cohort of 33 Spanish patients. Based on complementation testing, we selected 15 patients as defective in E1beta, 10 in E1alpha, seven in E2l; one remains unclassified. 92.5% of alleles have been characterized, and the mutational spectrum includes 36 different sequence variations presumably leading to loss-of-function, 15 changes in the BCKDHA, 14 in the BCKDHB, and seven in the DBT genes. Twenty-four changes are novel. The mutational profile is heterogeneous with no prevalent sequence variations detected, except for the E1beta mutation, c.487G>T (p.Glu163X), which appears on six out of 30 disease alleles analyzed. Approximately 30% of the patients included in this study showed a variant MSUD phenotype. That included 50% of the patients identified as EIa and at least four out of seven of those selected as EII. Precise genotypes as c.[647C>T]+[889C>T] for the EIa and c.[827T>G ]+[1349C>A] for the EII appeared associated to the mildest presentations of the disease.

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Section: Resultssupporting

confidence: 86%

Mutational spectrum of maple syrup urine disease in Spain

et al. 2006

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“…This distribution of mutations over the three BCKD genes confirms the results reported by Nellis and Danner (2001). Quite the opposite was reported before by other groups who identified the majority of MSUD mutations in the E1α-gene (type Ia) or the E2-gene (type II) (Chuang and Shih, 2001 …”

Section: Discussionsupporting

confidence: 89%

Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease

et al. 2003

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Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder of panethnic distribution caused by a deficiency of the activity of branched-chain alpha-ketoacid dehydrogenase (BCKD) complex. Mutations in the human BCKD genes E1alpha (BCKDHA), E1beta (BCKDHB) and E2 (DBT) are known to result in MSUD, referred to as type Ia, Ib and II mutations respectively. In this study 16 patients with the classic severe form of MSUD and three patients with milder variant forms of the disease were investigated for mutations in the E1alpha-, E1beta- and E2-gene by single-strand conformation polymorphism (SSCP) analysis and DNA sequencing. The patients' clinical and biochemical phenotypes were well characterized. One novel type Ia missense mutation, eight novel type Ib (three missense, two nonsense, two small deletions, one small duplication) and three novel type II (two missense, one splice site) mutations were identified in patients. Moreover, eleven previously described mutations were detected: five type Ia (four missense, one nonsense), three type Ib mutations (two missense, one nonsense) and three type II mutations (two missense, one small deletion). Fourteen patients are homozygous for one single mutation, five patients are compound-heterozygous for two different mutations affecting one of the three genes. Thus, in all 19 patients the identified mutations can most probably be considered the molecular basis of the disease.

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“…The lack of PDH E1β mutations is particularly striking in comparison with the closely related subunit of the branched chain α-ketoacid dehydrogenase (BCKD). In patients with maple syrup urine disease attributable to defects in the E1 component of this enzyme complex, mutations are almost equally distributed between the genes for the E1α and E1β subunits (Nellis and Danner 2001). The most likely explanation for this difference lies in the location of the gene for the PDH E1α subunit on the X chromosome and the high frequency of manifestation of the disease in heterozygous females (Brown et al 1994).…”

Section: Discussionmentioning

confidence: 99%

Mutations in the gene for the E1? subunit: a novel cause of pyruvate dehydrogenase deficiency

et al. 2004

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We describe two unrelated patients with pyruvate dehydrogenase (PDH) deficiency attributable to mutations in the gene encoding the E1beta subunit of the complex. This is a previously unrecognised form of PDH deficiency, which most commonly results from mutations in the X-linked gene for the E1alpha subunit. Both patients had reduced immunoreactive E1beta protein and both had missense mutations in the E1beta gene. Activity of the PDH complex was restored in cultured fibroblasts from both patients by transfection and expression of the normal E1beta coding sequence.

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Gene Preference in Maple Syrup Urine Disease

Cited by 65 publications

References 18 publications

Mutational spectrum of maple syrup urine disease in Spain

Mutational spectrum of maple syrup urine disease in Spain

Identification of twelve novel mutations in patients with classic and variant forms of maple syrup urine disease

Mutations in the gene for the E1? subunit: a novel cause of pyruvate dehydrogenase deficiency

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