{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,2]],"date-time":"2025-12-02T15:19:22Z","timestamp":1764688762226},"reference-count":21,"publisher":"Wiley","issue":"S3","license":[{"start":{"date-parts":[[2010,4,30]],"date-time":"2010-04-30T00:00:00Z","timestamp":1272585600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J of Inher Metab Disea"],"published-print":{"date-parts":[[2010,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mutations in any of the three different genes\u2014<jats:italic>BCKDHA<\/jats:italic>, <jats:italic>BCKDHB<\/jats:italic>, and <jats:italic>DBT<\/jats:italic>\u2014encoding for the E1\u03b1, E1\u03b2, and E2 catalytic components of the branched\u2010chain \u03b1\u2010ketoacid dehydrogenase complex can cause maple syrup urine disease (MSUD). Disease severity ranges from the classic to the mildest variant types and precise genotypes, mostly based on missense mutations, have been associated to the less severe presentations of the disease. Herein, we examine the consequences at the messenger RNA (mRNA) level of the novel intronic alteration c.288+9C&gt;T found in heterozygous fashion in a <jats:italic>BCKDHA<\/jats:italic> variant MSUD patient who also carries the nucleotide change c.745G&gt;A (p.Gly249Ser), previously described as a severe change. Direct analysis of the processed transcripts from the patient showed\u2014in addition to a low but measurable level of normal mRNA product\u2014an aberrantly spliced mRNA containing a 7\u2010bp fragment of intron 2, which could be rescued when the patient's cells were treated with emetine. This aberrant transcript with a premature stop codon would be unstable, supporting the possible activation of nonsense\u2010mediated mRNA decay pathway. Consistent with this finding, minigene splicing assays demonstrated that the point mutation c.288+9C&gt;T is sufficient to create a cryptic splice site and cause the observed 7\u2010bp insertion. Furthermore, our results strongly suggest that the c.288+9C&gt;T allele in the patient generates both normal and aberrant transcripts that could sustain the variant presentation of the disease, highlighting the importance of correct genotyping to establish genotype\u2013phenotype correlations and as basis for the development of therapeutic interventions.<\/jats:p>","DOI":"10.1007\/s10545-010-9077-7","type":"journal-article","created":{"date-parts":[[2010,4,29]],"date-time":"2010-04-29T07:19:04Z","timestamp":1272525544000},"page":"191-198","source":"Crossref","is-referenced-by-count":6,"title":["Functional characterization of the novel intronic nucleotide change c.288+9C&gt;T within the <i>BCKDHA<\/i> gene: understanding a variant presentation of maple syrup urine disease"],"prefix":"10.1002","volume":"33","author":[{"given":"Paula","family":"Fern\u00e1ndez\u2010Guerra","sequence":"first","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares, Dpto. Biol. Mol., Centro Biolog\u00eda Molecular\u2010SO UAM\u2010CSIC Universidad Aut\u00f3noma de Madrid, Campus Cantoblanco F. Ciencias. Modulo 10 Madrid 28049 Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER) Instituto de Salud Carlos III Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosa","family":"Navarrete","sequence":"additional","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares, Dpto. Biol. Mol., Centro Biolog\u00eda Molecular\u2010SO UAM\u2010CSIC Universidad Aut\u00f3noma de Madrid, Campus Cantoblanco F. Ciencias. Modulo 10 Madrid 28049 Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER) Instituto de Salud Carlos III Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kara","family":"Weisiger","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics University of California\u2013San Fancisco (UCSF) San Francisco CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lourdes R.","family":"Desviat","sequence":"additional","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares, Dpto. Biol. Mol., Centro Biolog\u00eda Molecular\u2010SO UAM\u2010CSIC Universidad Aut\u00f3noma de Madrid, Campus Cantoblanco F. Ciencias. Modulo 10 Madrid 28049 Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER) Instituto de Salud Carlos III Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Seymour","family":"Packman","sequence":"additional","affiliation":[{"name":"Division of Medical Genetics, Department of Pediatrics University of California\u2013San Fancisco (UCSF) San Francisco CA USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magdalena","family":"Ugarte","sequence":"additional","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares, Dpto. Biol. Mol., Centro Biolog\u00eda Molecular\u2010SO UAM\u2010CSIC Universidad Aut\u00f3noma de Madrid, Campus Cantoblanco F. Ciencias. Modulo 10 Madrid 28049 Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER) Instituto de Salud Carlos III Madrid Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pilar","family":"Rodr\u00edguez\u2010Pombo","sequence":"additional","affiliation":[{"name":"Centro de Diagn\u00f3stico de Enfermedades Moleculares, Dpto. Biol. Mol., Centro Biolog\u00eda Molecular\u2010SO UAM\u2010CSIC Universidad Aut\u00f3noma de Madrid, Campus Cantoblanco F. Ciencias. 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