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Biomedical subjects

M Baiget

Publications and source records attributed to M Baiget.

At least 37 records · Page 2Linked to original sources
PubMed2002

Survival and respiratory decline are not related to homozygous SMN2 deletions in ALS patients.

The presence of the SMN2 deletion in 124 patients with ALS was investigated. Eleven patients had the homozygous deletion of SMN2 (8.8%) in comparison with 20 of 200 (10%) of the healthy control population. No significant differences in sex, age at onset, initial symptoms, form of inheritance, decline in ventilatory function, or survival time were found between patients with and without the deletion. The hypothesis that SMN2 is a prognostic factor in sporadic or familial ALS was not confirmed in this study.

Adult↗
PubMed2002

Modifier genes in haemophilia: their expansion in the human genome.

Mutations in factor VIII and IX genes have a determinant effect on the severity of haemophilia. Modulation of clinical manifestations depends on other genetic factors, including modifier genes. In the context of haemophilia, such genes could be the ones involved in thrombophilia. Factor V Leiden and prothrombin 20210A were studied as possible phenotypic modifiers. Inhibitor development after therapeutic factor replacement depends on the type of mutation and on the genetic factors related to the immune response of each patient. The study of all these variants in haemophiliacs constitutes an important step in prevention, prognosis and therapeutic alternatives of the disease.

Factor VIII↗
PubMed2002

[Interest in the study of genetic variants of the promoter region of the UGT1A1 gene in neonatal jaundice].

BACKGROUND: A relationship between polymorphism in the promoter region of the UGT1A1 gene (associated with Gilbert's syndrome) and the development of jaundice has recently been demonstrated. This polymorphism is due to (TA)7 instead of wild-type (TA)6. OBJECTIVE: To investigate the relationship between Gilbert's syndrome and neonatal jaundice by evaluating the distribution of (TA)7 in a population of newborns. METHODS: A total of 136 newborns were studied: 21 had neonatal jaundice, 69 were healthy and the remaining newborns had various diseases. DNA from each patient was used to amplify, by polymerase chain reaction, the promoter region of the UGT1A1 gene, which flanks the TATA box where the polymorphism is located. RESULTS: In the group without jaundice, 53 % of the newborns were normal (6/6 genotype), 40 % were 6/7 and 7 % were 7/7. In the group with jaundice, 33 % of the newborns were normal, 53 % were heterozygous (6/7) and 14 % were homozygous (7/7). Comparison of the groups revealed that the prevalence of UGTA1A polymorphism tended to be greater among jaundiced newborns (p 0.09). CONCLUSION: The results of this study suggest that there is a relationship between neonatal jaundice and Gilbert's syndrome among the Spanish population. These results, together with those of other authors, suggest that genetic screening for Gilbert's syndrome should be included in the investigation of neonatal jaundice in our population. Further studies with a greater number of subjects would determine the exact relationship between marked neonatal jaundice and IGTA1A polymorphism. Key words:

Gilbert Disease↗
PubMed2002

Prenatal diagnosis for risk of spinal muscular atrophy.

OBJECTIVES: Prenatal diagnosis of spinal muscular atrophy is usually performed in high risk couples by detection of a homozygous deletion in the survival motor neurone gene (SMN1). However, other relatives at risk of being carriers very often request genetic counselling and the possibility of prenatal diagnosis. The aim of this study was to validate a SMN1 gene quantitative test to help the couples formed by one spinal muscular atrophy carrier and a partner of the general population (1/200 potential risk) to achieve a less ambiguous risk result for the pregnancy. DESIGN: Spinal muscular atrophy carrier studies in at-risk individuals. SETTING: Department of Genetics and Gynaecology and Obstetrics in a large university hospital. POPULATION: Seventy-nine obligate carriers (more than one affected child with deletion in the offspring) and 58 non-carriers (relatives of spinal muscular atrophy families defined by marker studies) were tested to set up a quantitative analysis. The method was applied in different situations in 126 members from 34 families with spinal muscular atrophy patients. METHODS: DNA studies of the SMNI gene by marker analysis and quantitative assay. MAIN OUTCOME MEASURES: To determine double (non-carrier) or single dose (carrier) of exon 7 of the SMN1 gene in relatives of spinal muscular atrophy patients. Bayesian calculation of risk. RESULTS: The sensitivity and specificity of the method were 96% and 100%, respectively. Studies on different couples with an a priori risk of 1/200 allowed us to reduce the final risk to 1/5000 or to increase it to 1/4. CONCLUSIONS: The quantitative method can be used to achieve a less ambiguous risk in pregnancies with a 1/200 risk and in families where no sample is available to study the index case. Screening of gamete donors when the recipient is a known carrier should also be considered.

Cyclic AMP Response Element-Binding Protein↗
PubMed2001

Loss of heterozygosity on chromosome 13q12-q14, BRCA-2 mutations and lack of BRCA-2 promoter hypermethylation in sporadic epithelial ovarian tumors.

BACKGROUND: BRCA-1 and BRCA-2 are tumor suppressor genes in familial breast-ovarian carcinoma syndrome. BRCA-1 is also a tumor suppressor gene in sporadic ovarian carcinomas. However, the role of BRCA-2 in sporadic ovarian tumors remains unclear. METHODS: DNA from 52 patients with clinically apparent sporadic ovarian tumors was extracted from blood and from fresh-frozen tumor tissue and normal tissue (10 benign, 7 borderline, and 35 malignant). Loss of heterozygosity (LOH) was analyzed in six microsatellite loci on chromosome 13q. BRCA-2 mutations were detected by single-strand conformation polymorphism analysis and the protein truncation test. BRCA-2 promoter methylation was evaluated by methylation specific polymerase chain reaction analysis. RESULTS: LOH on chromosome 13q12-q14 was identified in 16 tumors (30.8%): Fifteen of these tumors were carcinomas (15 of 35 tumors; 42.8%) and one was a borderline tumor. LOH was frequent in carcinomas with serous differentiation (12 of 16 tumors; 75%). LOH on chromosome 13q12-q14 coexisted with LOH on chromosome 17q in 10 carcinomas. BRCA-2 methylation was not detected in any tumor. BRCA-2 mutations were found in three tumors (one somatic nonsense and two germline frameshift). BRCA-2 fulfilled the two hits for a tumor suppressor gene in these three tumors; in one of them, a BRCA-1 tumor suppressor role had been demonstrated previously. CONCLUSIONS: The results suggest that BRCA-1 and BRCA-2 may act synergically in sporadic ovarian carcinomas with serous differentiation. The demonstration of BRCA-2 germline mutations in patients with ovarian carcinoma with LOH on chromosome 13q12-q14 and lack of a remarkable family history of cancer suggest that the proportion of ovarian carcinomas that result from hereditary predisposition may be higher than previously estimated.

BRCA2 Protein↗
PubMed2001

[Clinical and pathological characteristics and clinical course of patients with breast cancer and BRCA1/BRCA2 mutations].

BACKGROUND: Clinico-pathological differences between BRCA1 or BRCA2 mutation-associated breast cancer (BC) and sporadic BC are little known. PATIENT AND METHODS: We analysed the clinico-pathological characteristics and clinical follow-up of 30 patients with BC. BRCA1 and BRCA2 mutations were detected by SSCP and PTT. RESULTS: There were no differences in age, size or nodal status at the time of diagnosis. Mammography features were more heterogeneous in BRCA2 than in BRCA1 BC. All BRCA1 mutation-associated BC corresponded to infiltrating ductal carcinomas (20% medullary carcinomas) with a more aggressive pathological behavior. The frequency of local recurrences was 14% in BRCA1 and 20% in BRCA2. Contralateral BC and ovarian cancer (OC) were observed in 27% and 20% of BRCA1 cases, respectively, and 6% and 6% of BRCA2 cases. The median follow-up in BRCA1 and BRCA2 BC was 131 and 54 months, respectively. CONCLUSIONS: There were no differences in age at diagnosis and stage between BRCA1 and BRCA2 breast cancer. The mammographic pattern in BRCA2 was more heterogeneous. BRCA1 mutations were associated with more aggressive histopathologic findings and a higher risk of a second BC and OC.

Adult↗
PubMed2001

[Molecular analysis of the RPE65 gene in 72 Spanish families with autosomal recessive retinitis pigmentosa].

BACKGROUND: Autosomal recessive retinitis pigmentosa (arRP) is the most common form of retinitis pigmentosa (RP). It is characterized by a high degree of allelic and non-allelic genetic heterogeneity. Previously,it has been demonstrated that the RPE65 gene is responsible for 2% recessive or isolated RP cases and 16% Leber's congenite amaurosis cases. Although the concrete function of RPE65 is unknown as yet, it has been found to be involved in vitamin A metabolism and rhodopsin regeneration. PATIENTS AND METHOD: We studied the involvement of the RPE65 gene in 72 arRP Spanish families by means of indirect molecular and mutation analysis. RESULTS: The results obtained using the intragenic microsatellite marker D1S2803 allowed us to exclude RPE65 as the causative gene of the disease in 80.5% of the families studied. Three new variants of the RPE65 gene have been identified: IVS6-43delA, IVS6-42delT and IVS6-33CG. We found that IVS6-33C-->G was a common polymorphism. The other variants, namely IVS6-43delA and IVS6-42delT, were not identified in 150 control chromosomes studied. The segregation analysis of IVS6-42delT variant seemed to exclude it as being involved in the disease. CONCLUSIONS: Our results argue against the involvement of RPE65 gene in the families studied, indicating that the prevalence of RPE65 abnormalities in arRP Spanish families may be lower than that observed in other populations.

Carrier Proteins↗
PubMed2001

Frequency and stability of the myotonic dystrophy type 1 premutation.

BACKGROUND: Myotonic dystrophy type 1 (DM1) is associated with the expansion of an unstable CTG repeat. Larger alleles are associated with a more severe form of the disease and almost always increase in length from one generation to the next, accounting for the clinical anticipation characteristic of DM1. As such, expanded alleles are rapidly lost from the population. However, the incidence of the disease appears to remain constant. It was the authors' aim to determine the frequency and germline stability of the DM1 premutation alleles that give rise to new DM1 families. METHODS: The authors measured the size of the DM1 CTG repeat in blood DNA derived from a large number of individuals in DM1 families, including distant and unaffected relatives. RESULTS: It was determined that DM1 premutation alleles can be identified both in distant relatives of DM1 probands and more rarely in unaffected spouses. These premutation alleles are not directly associated with a clinical phenotype in the carrier but are highly unstable and liable to expand in succeeding generations, particularly when transmitted by a man. In addition, the authors observed occasional expansion-biased instability of alleles within the high end of the normal size range. CONCLUSIONS: Individuals carrying premutation alleles are at high risk of having affected offspring within a limited number of generations. Such data indicate that premutation alleles cannot be the long-term source of new DM1 families, which must ultimately arise from mutations of alleles within the upper normal size range.

Adult↗
PubMed2001

Mutations P51U and G122E in retinal transcription factor NRL associated with autosomal dominant and sporadic retinitis pigmentosa.

Retinitis pigmentosa (RP) is the most frequent form of inherited retinopathy. RP is genetically heterogeneous with autosomal dominant, autosomal recessive and X-linked forms. Autosomal dominant retinitis pigmentosa (adRP) accounts for about 20-25% of all RP cases. At least ten adRP loci have so far been mapped. However, mutations causing adRP have been identified only in four retina-specific genes: RHO (encoding rhodopsin) in approximately 20% of adRP families, peripherin/RDS (3-5% of adRP) and recently RP1 (Pierce et al., 1999, Sulivan et al., 1999) and NRL gene. Only one mutation in the NRL gene causing adRP has so far been reported (Bessant et al., 1999). Here we report a novel mutation Pro51Leu in an adRP Spanish family supporting that mutation in NRL is the cause of adRP. A second missense mutation Gly122Glu has been observed in a simplex RP patient that may represent a sporadic case of retinitis pigmentosa. Hum Mutat 17:520, 2001.

Base Sequence↗
PubMed2001

The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript.

In a BRCA1 screening in familial breast cancer carried out in different centres in Spain, France, and United Kingdom, a missense mutation 330A>G which results in a Arg to Gly change at codon 71 (R71G) was independently identified in 6 families, all of them with Spanish ancestors. This residue coincides with the -2 position of the exon 5 donor splice site. We further investigated the effect of this base substitution on the splicing of BRCA1 mRNA. The sequence analysis of the cDNA indicated that 22 bp of exon 5 were deleted, creating with the first bases of exon 6 a termination codon at position 64, which results in a truncated protein. The BRCA1 haplotype of the R71G carrier patients and Spanish controls was analysed by use of six microsatellites located within or near BRCA1. Our results are consistent with the possibility that these families shared a common ancestry with BRCA1 R71G being a founder mutation of Spanish origin.

Age of Onset↗
PubMed2001

Characterisation of SMN hybrid genes in Spanish SMA patients: de novo, homozygous and compound heterozygous cases.

Autosomal recessive spinal muscular atrophy (SMA) is classified, by age of onset and maximal motor milestones achieved, into type I (severe form), type II (intermediate form) and type III (mild/moderate form). SMA is caused by mutations in the survival motor neuron telomeric gene (SMN1) and a centromeric functional copy of this gene (SMN2) exists, both genes being located at 5q13. Homozygous deletion of exons 7 and 8 of SMN1 has been detected in approx 85% of Spanish SMA patients regardless of their phenotype. Nineteen cases with the sole deletion of exon 7 but not exon 8 (2 cases of type I, 13 cases of type II, four cases of type III) were further analysed for the presence of SMN2-SMN1 hybrid genes. We detected four different hybrid structures. Most of the patients were carriers of a hybrid structure: centromeric intron 6- centromeric exon 7- telomeric exon 8 (CCT), with or without neuronal apoptosis-inhibitor protein (NAIP). In two patients, a different hybrid structure, viz. telomeric intron 6- centromeric exon 7- telomeric exon 8 (TCT), was detected with or without NAIP. A phenotype-genotype correlation comparing the different structures of the hybrid alleles was delineated. Type I cases in our series are attributable to intrachromosomal deletion with a smaller number of SMN2 copies. Most cases with hybrid genes are type II occurring by a combination of a classical deletion in one chromosome and a hybrid gene in the other. Type III cases are closely associated with homozygozity or compound heterozygozity for hybrid genes resulting from two conversion events and have more copies of hybrid genes and SMN2 than type I or II cases.

Alleles↗
PubMed2001

BRCA2 mutation analysis of 87 Spanish breast/ovarian cancer families.

BACKGROUND: It is estimated that about 5% -10% of breast cancer (BC) cases is due to inherited predisposition. Early works reported that 45%-50% of site-specific BC families had BRCA1 mutations and 25%-35% BRCA2 mutations. However, these percentages could have been overestimated and likely vary among the populations studied. PATIENTS AND METHODS: We analysed the BRCA2 gene in 87 Spanish breast/ovarian cancer families in which the BRCA1 mutation screening was negative. RESULTS: We detected 15 (17.2%) disease-causing mutations and 11 polymorphisms and unclassified variants. Four mutations were recurrent, and five were novel. Seven (47%) mutations were found in site-specific female BC families, five (33%) in families with OC cases, and three (20%) mutations in families with male BC cases. There was incomplete penetrance of the mutations in some families, and considerable phenotypic variations with respect to the age of diagnosis and cancer types. CONCLUSIONS: The percentage of mutations detected reinforces the possibility that some of these families have mutations in genes other than BRCA1 or BRCA2 that confer lower BC risks.

Adult↗
PubMed2001

Clinical and pathological findings of BRCA1/2 associated breast cancer.

It is not known if the behaviour of hereditary breast cancer (HBC) differs from that of sporadic breast cancer (BC). The aim of the present study was to analyze clinical-pathological characteristics in patients with BRCA1/2-mutation associated to BC. These data could be useful in the management of HBC. This study includes 17 patients with BC in whom a germ-line BRCA1/2-mutation was diagnosed. The patients were from 10 different families, and four patients had no family history of BC or ovarian cancer (OC). The study of mutations was with the protein truncation test (exon 11 for BRCA1, exons 10 and 11 for BRCA2) and sequencing (the rest of exons). At diagnosis the mean age was 37 years (28-54). Only 3/17 patients presented with involvement of axillary nodes; no patient was diagnosed with metastatic disease. All cases were infiltrating ductal carcinoma; two of them were medullary carcinoma. Histological grade was available in 13/17 cases, with grade III being the most frequent (12/13). Hormonal receptors were negative in 8/10 patients. The mean follow-up was 129 months (23-223). There were three local recurrences at 17, 108 and 151 months; and two distant relapses at 15 months (complete remission) and 92 months. There were three diagnosed contralateral BC. Hereditary breast cancer has malignant pathological features, but the clinical behaviour may be less aggressive than sporadic breast cancer in the same age group.

Journal Article↗
PubMed2001

Evaluation of RLBP1 in 50 autosomal recessive retinitis pigmentosa and 4 retinitis punctata albescens Spanish families.

Defects in retinal vitamin A metabolism or in genes expressed in the retinal pigment epithelium (RPE) are related to nonsyndromic retinitis pigmentosa (RP). The RLBP1 gene encodes the cellular retinaldehyde-binding protein which, in the RPE and Müller cells of the retina, is thought to play a role in retinoid metabolism and visual pigment regeneration. We describe a study of the involvement of the RLBP1 gene in 50 autosomal recessive retinitis pigmentosa (ARRP) and four retinitis punctata albescens Spanish families. Cosegregation and homozygosity studies using an intragenic polymorphism and three close markers (D15S116, D15S127, and D15S130) ruled out RLBP1 as the cause of ARRP in 26 pedigrees. In the remaining families, SSCP analysis of the coding region and sequencing of the abnormal migrating bands did not detect any disease-causing mutation. These results indicate that mutations in the RLBP1 gene are not responsible for the ARRP or retinitis punctata albescens in this set of Spanish families. We did, however, identify two frequent polymorphisms (3'UTR + 167 G > T, T: 0.23 and G: 0.77; IVS6 + 20 T > C, T: 0.36 and C: 0.64), a silent substitution (S218S), and a rare variant (5'UTR-101 G > A).

Carrier Proteins↗