Molecular and structural analyses of maple syrup urine disease and identification of a founder mutation in a Portuguese Gypsy community

Quental, Sofia; Macedo-Ribeiro, Sandra; Matos, R M Albuquerque de; Vilarinho, Laura; Martins, Esmeralda; Teles, Elisa Leão; Rodrigues, Esmeralda; Diogo, Luísa; Garcia, Paula; Eusébio, Filomena; Gaspar, Ana; Sequeira, Sílvia; Furtado, Fátima; Lança, Isabel; Amorim, António; Prata, Maria João

doi:10.1016/j.ymgme.2008.02.008

Cited by 32 publications

(23 citation statements)

References 21 publications

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“…Mutation, p.Lys313Asn present in patient (P4) presented withclassical phenotype while patient (P15) had intermediate phenotype. This mutation has been reported previously in a Portuguese patient with variant (non-classical) MSUD phenotype[Quental et al, 2008].…”

supporting

confidence: 65%

Identification of mutations, genotype–phenotype correlation and prenatal diagnosis of maple syrup urine disease in Indian patients

Gupta

Bijarnia-Mahay

Saxena

et al. 2015

European Journal of Medical Genetics

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supporting

confidence: 65%

Identification of mutations, genotype–phenotype correlation and prenatal diagnosis of maple syrup urine disease in Indian patients

Gupta

Bijarnia-Mahay

Saxena

et al. 2015

European Journal of Medical Genetics

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“…Recently we reported on a Portuguese patient affected with MSUD in whom the systematic failure to amplify the genomic region encompassing exons 2, 3 and 4 of the gene BCKDHA led us to suspect that the molecular defect causing his MSUD phenotype was a large deletion in BCKDHA (Quental et al 2008). Analysis of the cDNA region normally containing exons 1 to 5 confirmed the deletion of exons 2, 3 and 4, corroborating our previous deduction.…”

Section: Resultssupporting

confidence: 83%

“…The mutation analysis that led to detection of the BCKDHA deletion in this child was previously described in a work on the molecular characterization of MSUD in Portuguese patients (Quental et al 2008).…”

Section: Mutation Analysismentioning

confidence: 93%

Maple syrup urine disease due to a new large deletion at BCKDHA caused by non‐homologous recombination

Quental

Martins

Vilarinho

et al. 2008

J of Inher Metab Disea

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Maple syrup urine disease (MSUD) is a rare disorder of branched-chain amino acid (BCAA) metabolism caused by the defective function of branched-chain α-ketoacid dehydrogenase complex (BCKD). Many MSUD-causing mutations have already been described in genes that encode the complex (BCKDHA, BCKDHB and DBT), but up to now only four large deletions are known, all located in the DBT gene. In a previous study we identified a Portuguese MSUD patient with a homozygous deletion of exons 2, 3 and 4 at the BCKDHA gene; however, the corresponding breakpoints and, consequently, the exact deletion extension were not identified. Here, using long-range PCR and sequencing methodologies we were able to refine the characterization of this gross rearrangement. A genomic DNA loss of about 13.8 kb was detected, starting at intron 1 and ending at intron 4, thus encompassing exons 2, 3 and 4. Molecular characterization showed that the deletion junction contained a short sequence whose motif was CGGG. Since this motif is present in introns 1 and 4 of normal genomic DNA, we have hypothesized that non-homologous recombination was the mechanism underlying the identified large deletion, within which the CGGG could be derived either from intron 1 or from intron 4.

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“…For example, intragenic deletion and duplication mutations had not been documented in MSUD patients previously. Molecular characterization of MSUD alleles has a ϳ95% mutation detection rate with a mutation spectrum of ϳ95% point mutations; the remaining 5% were considered uncharacterized mutations, 35,36 and large and single-exon deletions and duplications had not been seen before. Here we present for the first time two cases of multiexon deletion and duplication mutations in the BCKDHB gene, identified in patient T6 and T5, respectively.…”

Section: Discussionmentioning

confidence: 99%

Targeted comparative genomic hybridization array for the detection of single- and multiexon gene deletions and duplications

Tayeh

Chin

Miller

et al. 2009

Genetics in Medicine

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Purpose: To develop a high resolution microarray based method to detect single-and multiexons gene deletions and duplications. Methods: We have developed a high-resolution comparative genomic hybridization array to detect single-and multiexon deletions and duplications in a large set of genes on a single microarray, using the NimbleGen 385K array with an exon-centric design. Results: We have successfully developed, validated, and implemented a targeted gene comparative genomic hybridization arrays for detecting single-and multiexon deletions and duplication in autosomal and X-linked diseaseassociated genes. Conclusion: The comparative genomic hybridization arrays can be adopted readily by clinical molecular diagnostic laboratories as a rapid, cost-effective, highly sensitive, and accurate approach for the detection of single-and multiexon deletions or duplications, particularly in cases where direct sequencing fails to identify a mutation. Genet Med 2009:11(4):232-240.

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Molecular and structural analyses of maple syrup urine disease and identification of a founder mutation in a Portuguese Gypsy community

Cited by 32 publications

References 21 publications

Identification of mutations, genotype–phenotype correlation and prenatal diagnosis of maple syrup urine disease in Indian patients

Identification of mutations, genotype–phenotype correlation and prenatal diagnosis of maple syrup urine disease in Indian patients

Maple syrup urine disease due to a new large deletion at BCKDHA caused by non‐homologous recombination

Targeted comparative genomic hybridization array for the detection of single- and multiexon gene deletions and duplications

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