RESUMEN
Maple syrup urine disease (MSUD) is a rare disorder of branched-chain amino acids (BCAA) metabolism caused by the defective function of branched-chain α-ketoacid dehydrogenase complex (BCKD). The disease causal mutations can occur either in BCKDHA, BCKDHB or DBT genes encoding respectively the E1α, E1ß and E2 subunits of the complex. In this study we report the molecular characterization of 3 Tunisian patients with the classic form of MSUD. Two novel putative mutations have been identified: the alteration c.716A>G (p.Glu239Gly) in BCKDHB and a small deletion (c.1333_1336delAATG; p.Asn445X) detected in DBT gene.
Asunto(s)
3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/genética , Enfermedad de la Orina de Jarabe de Arce/patología , Mutación/genética , Oxidorreductasas/genética , Eliminación de Secuencia/genética , Femenino , Humanos , Recién Nacido , Masculino , Enfermedad de la Orina de Jarabe de Arce/enzimología , Enfermedad de la Orina de Jarabe de Arce/genética , Pronóstico , TúnezRESUMEN
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.
Asunto(s)
3-Metil-2-Oxobutanoato Deshidrogenasa (Lipoamida)/genética , Enfermedad de la Orina de Jarabe de Arce/genética , Recombinación Genética , Eliminación de Secuencia , Aminoácidos de Cadena Ramificada/sangre , Secuencia de Bases , Biomarcadores/sangre , Análisis Mutacional de ADN , Exones , Predisposición Genética a la Enfermedad , Humanos , Recién Nacido , Intrones , Masculino , Enfermedad de la Orina de Jarabe de Arce/sangre , Enfermedad de la Orina de Jarabe de Arce/diagnóstico , Enfermedad de la Orina de Jarabe de Arce/enzimología , Datos de Secuencia Molecular , Motivos de Nucleótidos , Fenotipo , Reacción en Cadena de la Polimerasa , Regulación hacia ArribaRESUMEN
Genetic data on the thiopurine S-methyltransferase (TPMT) polymorphism were obtained in population samples from Cabinda and Mozambique (located in the western and eastern coasts of sub-Saharan Africa, respectively). The overall frequency of TPMT-deficient alleles was 5.6% in Mozambique and 6.3% in Cabinda. Accordingly, one out of the 103 individuals from Cabinda tested had a genotype associated with TPMT deficiency, yielding a frequency that is threefold higher than heretofore reported in any population. In addition, in both Cabinda or Mozambique, TPMT*8 accounted for a significant proportion of non-functional alleles (nearly 40% in Cabinda). Since the substitution defining TPMT*8 seems to be highly specific of sub-Saharan Africa populations and given the fact it has not been integrated into the set of single nucleotide polymorphisms routinely tested for TPMT, a re-design of molecular screenings should be considered in the future in order to avoid serious underestimates of TPMT deficiency when the enzymatic profiles in populations are unknown.