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Bueno M.A.,Hospital Universitario Virgen Del Rocio | Gonzalez-Lamuno D.,Paediatric Nephrology and Metabolism Unit | Delgado-Pecellin C.,Hospital Universitario Virgen Del Rocio | Aldamiz-Echevarria L.,Hospital de Cruces | And 3 more authors.
Journal of Human Genetics | Year: 2013

The aim of this study was to identify the most common genotypes in the phenylketonuria (PKU) population of Andalusia, assessing the correlation with the phenotype and the usefulness in predicting the response to treatment with tetrahydrobiopterin. We conducted a retrospective observational study between January 1980 and January 2010 in 147 Andalusian PKU patients assessing phenotype, genotype and response to a 24-h BH4 loading test. Our cohort of patients exhibited 65 different mutations, 69.2% corresponding to the missense type, in a total of 123 different genotypes. IVS10nt-11g>a was the most common mutation (10.9%). Four novel missense mutations were identified: p.L258P; p.E66K, p.R155C and p.P122S. Although generally there is a good genotype-phenotype correlation, for eight of the repeated genotypes a slightly different phenotype was observed. In 96 PKU subjects BH4 challenge was carried out. Patients with previously reported unresponsive mutations on both alleles showed a negative response, while 95.5% (28/29) of the responsive patients carry at least one missense mutation previously associated to the BH4. Our data reveal a great genetic heterogeneity in the Andalusian population. Genotype is quite a good predictor of the phenotype and of the responsiveness to tetrahydrobiopterin, which is relevant for patient management and follow-up. © 2013 The Japan Society of Human Genetics All rights reserved. Source


Carrera I.A.,Neonatology Unit | Carrera I.A.,Center for Biomedical Research on Rare Diseases | Matthijs G.,Catholic University of Leuven | Perez B.,Center for Biomedical Research on Rare Diseases | And 3 more authors.
American Journal of Medical Genetics, Part A | Year: 2012

Congenital disorders of glycosylation (CDG) are due to either defects in the synthesis of the glycan moiety of glycoproteins or glycolipids and in the attachment of the glycans to proteins and lipids. Some 50 CDG have been identified. They represent a challenge for clinicians because most are multisystem diseases with a heterogeneous spectrum of clinical manifestations with involvement of any organ and system. We report on a patient with a mutation in the glycosyltransferase encoded by the DPAGT1 gene, an infrequent CDG. He showed severe fetal hypokinesia phenotype with decreased fetal movements and polyhydramnios. At birth he showed decreased facial expression, without nasolabial folds, soft long ears, U-shaped vermilion of the upper lip, thick skin, hypertrichosis, camptodactyly, moderate multiple contractures, hypotonia and severe hypokinesia, no spontaneous movements, and very limited movements with stimuli; he died at 11/2 months. Isoelectrofocusing of serum transferrin showed a type 1 pattern with increased asialo- and disialotransferrin. The study of the DPAGT1 gene showed he was a compound heterozygote for two novel point missense mutations [c.901C>T]+[c.1094T>G]. This phenotype expands the clinical features of the few DPATG1-CDG patients reported. © 2012 Wiley Periodicals, Inc.. Source


Gallego-Villar L.,Centro Of Diagnostico Of Enfermedades Moleculares | Perez-Cerda C.,Centro Of Diagnostico Of Enfermedades Moleculares | Perez B.,Centro Of Diagnostico Of Enfermedades Moleculares | Ugarte M.,Centro Of Diagnostico Of Enfermedades Moleculares | And 3 more authors.
Journal of Inherited Metabolic Disease | Year: 2013

Propionic acidemia (PA), caused by a deficiency of the mitochondrial biotin dependent enzyme propionyl-CoA carboxylase (PCC) is one of the most frequent organic acidurias in humans. PA is caused by mutations in either the PCCA or PCCB genes encoding the α- and β-subunits of the PCC enzyme which are assembled as an α6β6 dodecamer. In this study we have investigated the molecular basis of the defect in ten fibroblast samples from PA patients. Using homology modeling with the recently solved crystal structure of the PCC holoenzyme and a eukaryotic expression system we have analyzed the structural and functional effect of novel point mutations, also revealing a novel splice defect by minigene analysis. In addition, we have investigated the contribution of oxidative stress to cellular damage measuring reactive oxygen species (ROS) levels and apoptosis parameters in patient fibroblasts, as recent studies point to a secondary mitochondrial dysfunction as pathophysiological mechanism in this disorder. The results show an increase in intracellular ROS content compared to controls, correlating with the activation of the JNK and p38 signaling pathways. Highest ROS levels were present in cells harboring functionally null mutations, including one severe missense mutation. This work provides molecular insight into the pathogenicity of PA variants and indicates that oxidative stress may be a major contributing factor to the cellular damage, supporting the proposal of antioxidant strategies as novel supplementary therapy in this rare disease. © 2012 SSIEM and Springer Science+Business Media Dordrecht. Source


Couce M.L.,Hospital Clinico Universitario Of Santiago | Boveda M.D.,Hospital Clinico Universitario Of Santiago | Fernandez-Marmiesse A.,Hospital Clinico Universitario Of Santiago | Miras A.,Hospital Clinico Universitario Of Santiago | And 3 more authors.
Gene | Year: 2013

Knowledge of hyperphenylalaninemia (HPA) mutational spectrum in a population allows in many cases an accurate prediction of the phenotype and tetrahydrobiopterin (BH4) responsiveness, thus selecting an adequate treatment. In this work, we have performed the molecular characterization of 105 HPA patients from Galicia, in the northwest region of Spain, evaluating their phenotype and BH4 response. The mutational spectrum analysis showed 47 distinct mutations in 89 families, 37 of them (78.7%) corresponding to missense mutations. Six mutations account for 47.2% of all the investigated alleles, each one with a frequency ≥5% (IVS10-11G>A, p.R261Q, p.V388M, p.R176L, p.E280K, p.A300S). The most prevalent HPA mutations in Galicia are the common Mediterranean mutation IVS10-11G>A and p.R261Q, with frequencies of 13.8% and 10.5%, respectively. One novel mutation (p.K361Q; c.1081A>C) was also reported. Although a good genotype-phenotype correlation is observed, there is no exact correlation for some genotypes involving mutations p.R261Q, p.I65T or IVS10-11G>A. Forty seven patients were monitored for post-challenge BH4, establishing genotype-based predictions of BH4-responsiveness in all of them. All phenylketonuric patients with 2 nonresponsive mutations were unresponsive to BH4 and patients with mutations previously associated with BH4 responsiveness in the two alleles had a clear positive response to the test, with the exception of 5 patients with mutations p.R261Q, p.I65T and p.R68S. Our study supports a similar degree of heterogeneity of the HPA mutation spectrum in Galicia compared to reported data from Southern Europe. Patients carrying null mutations in both alleles showed the highest degree of concordance with the most severe phenotypes. Genotype is a good predictor of BH4 response. © 2013 Elsevier B.V. Source


Puisac B.,University of Zaragoza | Teresa-Rodrigo M.E.,University of Zaragoza | Arnedo M.,University of Zaragoza | Gil-Rodriguez M.C.,University of Zaragoza | And 6 more authors.
Molecular Genetics and Metabolism | Year: 2013

Eukaryotic cells can be protected against mutations that generate stop codons by nonsense-mediated mRNA decay (NMD) and/or nonsense-associated altered splicing (NAS). However, the processes are only partially understood and do not always occur. In this work, we study these phenomena in the stop codon mutations c.109G>T (p.Glu37*) and c.504_505delCT; the second and third most frequent mutations in HMG-CoA lyase deficiency (MIM #246450). The deficiency affects the synthesis of ketone bodies and produces severe disorders during early childhood. We used a minigene approach, real-time quantitative PCR and the inhibition of NMD by puromycin treatment, to study the effect of stop codons on splicing (NAS) and NMD in seven patients. Surprisingly, none of the stop codons studied appears to be the direct cause of aberrant splicing. In the mutation c.109G>T, the splicing is due to the base change G>T at position 109, which is critical and cannot be explained by disruption of exonic splicing enhancer (ESE) elements, by the appearance of exonic splicing silencer (ESS) elements which were predicted by bioinformatic tools or by the stop codons. Moreover, the mutation c.504_505delCT produces two mRNA transcripts both with stop codons that generate simultaneous NMD phenomena. The effects of the mutations studied on splicing seemed to be similar in all the patients. Furthermore, we report a Spanish patient with 3-hydroxy-3-methylglutaric aciduria and a novel missense mutation: c.825C>G (p.Asn275Lys). © 2013 Elsevier Inc. Source

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