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Biomedical subjects

A Reis

Publications and source records attributed to A Reis.

At least 127 records · Page 7Linked to original sources
PubMed1999

The Fanconi anemia group E gene, FANCE, maps to chromosome 6p.

Fanconi anemia (FA) is a genetically heterogeneous autosomal recessive disease with bone marrow failure and predisposition to cancer as major features, often accompanied by developmental anomalies. The cells of patients with FA are hypersensitive to DNA cross-linking agents in terms of cell survival and chromosomal breakage. Of the eight complementation groups (FA-A to FA-H) distinguished thus far by cell fusion studies, the genes for three-FANCA, FANCC, and FANCG-have been identified, and the FANCD gene has been localized to chromosome 3p22-26. We report here the use of homozygosity mapping and genetic linkage analysis to map a fifth distinct genetic locus for FA. DNA from three families was assigned to group FA-E by cell fusion and complementation analysis and was then used to localize the FANCE gene to chromosome 6p21-22 in an 18.2-cM region flanked by markers D6S422 and D6S1610. This study shows that data from even a small number of families can be successfully used to map a gene for a genetically heterogeneous disorder.

Cell Fusion↗
PubMed1999

Investigation of a family with autosomal dominant dilated cardiomyopathy defines a novel locus on chromosome 2q14-q22.

Dilated cardiomyopathy (DCM) is a leading cause of heart failure and the most frequent indication for heart transplantation in young patients. Probably >25% of DCM cases are of familial etiology. We report here genetic localization in a three-generation German family with 12 affected individuals with autosomal dominant familial DCM characterized by ventricular dilatation, impaired systolic function, and conduction disease. After exclusion of known DCM loci, we performed a whole-genome screen and detected linkage of DCM to chromosome 2q14-q22. Investigation of only affected individuals defines a 24-cM interval between markers D2S2224 and D2S2324; when unaffected individuals are also included, the critical region decreases to 11 cM between markers D2S2224 and D2S112, with a peak LOD score of 3.73 at recombination fraction 0 at D2S2339. The identification of an additional locus for familial autosomal dominant DCM underlines the genetic heterogeneity and may assist in the elucidation of the causes of this disease.

Adolescent↗
PubMed1999

Homozygosity mapping in families with Joubert syndrome identifies a locus on chromosome 9q34.3 and evidence for genetic heterogeneity.

Joubert syndrome is a rare developmental defect of the cerebellar vermis, with autosomal recessive inheritance. The phenotype is highly variable and may include episodic hyperpnea, abnormal eye movements, hypotonia, ataxia, developmental delay, and mental retardation. Even within sibships the phenotype may vary, making it difficult to establish the exact clinical diagnostic boundaries of Joubert syndrome. To genetically localize the gene region, we have performed a whole-genome scan in two consanguineous families of Arabian/Iranian origins, with multiple affected probands. In one family, we detected linkage to the telomeric region of chromosome 9q, close to the marker D9S158, with a multipoint LOD score of Z=+3.7. The second family did not show linkage to this region, giving a first indication of genetic heterogeneity underlying Joubert syndrome. These findings were supported by subsequent analysis of two smaller families-one compatible with linkage to 9q; the other, unlinked. We conclude that Joubert syndrome is clinically and genetically heterogeneous and that one locus maps to chromosome 9q.

Abnormalities, Multiple↗
PubMed1999

Mycophenolate mofetil versus cyclosporin A in high risk keratoplasty patients: a prospectively randomised clinical trial.

BACKGROUND/AIMS: The requirement for an effective, minimally toxic immunosuppressive agent remains a major obstacle to performing high risk corneal transplantation. Although therapy with cyclosporin A (CSA) allows superior graft survival, its use is limited because of a wide range of side effects. Mycophenolate mofetil (MMF) has been shown to be a safe and effective immunosuppressive agent following renal transplantation. This prospective, randomised clinical trial was carried out to investigate the efficacy and safety of MMF in preventing corneal allograft rejection. METHODS: Recipients of corneal transplants who were at high risk for graft failure were randomly assigned to either CSA or MMF immunosuppressive therapy. CSA was given in doses to achieve whole blood trough levels of 120-150 ng/ml. MMF was given in a daily dose of 2 g. Both therapy groups additionally received oral corticosteroids (fluocortolone 1 mg/kg) which were tapered and discontinued within the first 3 postoperative weeks. Patients were monitored closely for evidence of corneal graft rejection and adverse side effects. Drug efficacy was measured, primarily, by the number of patients who experienced at least one episode of clinical graft rejection. Safety analysis focused on reported adverse side effects and laboratory measurements. RESULTS: 41 patients were enrolled in the study. There was no statistically significant difference between the two groups. 20 patients received CSA and 21 patients received MMF. Two patients in each group showed evidence of acute graft rejection which could be treated effectively by corticosteroids. All corneal grafts remained clear throughout the follow up. CONCLUSIONS: In this study it was shown that MMF is just as effective as CSA in preventing acute rejection following high risk corneal transplantation. Mycophenolate mofetil represents a promising alternative therapeutic option in patients who are at high risk for corneal graft failure.

Adult↗
PubMed1999

Linkage of familial euthyroid goiter to the multinodular goiter-1 locus and exclusion of the candidate genes thyroglobulin, thyroperoxidase, and Na+/I- symporter.

Iodine deficiency is the most important etiological factor for euthyroid endemic goiter. However, family and twin pair studies also indicate a genetic predisposition for euthyroid simple goiter. In hypothyroid goiters several molecular defects in the thyroglobulin (TG), thyroperoxidase (TPO), and Na+/I- symporter (NIS) genes have been identified. The TSH receptor with its central role for thyroid function and growth is also a strong candidate gene. Therefore, we investigated a proposita with a relapsing euthyroid goiter and her family, in which several members underwent thyroidectomy for euthyroid goiter. Sequence analysis of the complementary DNA (cDNA) of the TPO and TSH receptor genes revealed several previously reported polymorphisms. As it is not possible to exclude a functional relevance for all polymorphisms, we opted for linkage analysis with microsatellite markers to investigate whether the candidate genes are involved in the pathogenesis of euthyroid goiter. The markers for the genes TG, TPO, and NIS gave two-point and multipoint logarithm of odds score analysis scores that were negative or below 1 for all assumed recombination fractions. As no significant evidence of linkage was found, we conclude that these candidate genes can be excluded as a major cause of the euthyroid goiters in this family. In contrast, we have found evidence for linkage of familial euthyroid goiter to the recently identified locus for familial multinodular nontoxic goiter (MNG-1) on chromosome 14q. The haplotype cosegregates clearly with familial euthyroid goiter. Our results provide the first confirmation for MNG-1 as a locus for nontoxic goiter.

Adolescent↗
PubMed1998

Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome.

Nijmegen breakage syndrome (NBS) is an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. Cells from NBS patients are hypersensitive to ionizing radiation with cytogenetic features indistinguishable from ataxia telangiectasia. We describe the positional cloning of a gene encoding a novel protein, nibrin. It contains two modules found in cell cycle checkpoint proteins, a forkhead-associated domain adjacent to a breast cancer carboxy-terminal domain. A truncating 5 bp deletion was identified in the majority of NBS patients, carrying a conserved marker haplotype. Five further truncating mutations were identified in patients with other distinct haplotypes. The domains found in nibrin and the NBS phenotype suggest that this disorder is caused by defective responses to DNA double-strand breaks.

Amino Acid Sequence↗
PubMed1998

A refined localization of two deleted regions in chromosome 6q associated with salivary gland carcinomas.

Deletions within chromosome 6 (6q25 to 6qter) are the most consistent structural change observed in salivary gland carcinomas. To better define the location of these deletions we investigated loss of heterozygosity (LOH) for 23 polymorphic markers within 19 salivary gland carcinomas covering several histological subtypes. LOH was observed in 47% of tumors, confirming previous reports that such losses are frequent and occur in almost all histological subtypes of tumors. The highest frequency of LOH was found at, or distal to, D6S437. Seven tumors had allelic losses for D6S297 and/or D6S37. A second peak of loss was also observed at D6S262 and D6S32. In some tumors we observed LOH in one or the other of these two regions. In other tumors we observed loss of both regions with retention of intervening loci. These data suggest that two small deletions commonly occur, one between D6S262 and D6S32 (estimated to cover less than 1.5 Mb) and another between D6S297 and D6S446 (estimated to cover approximately 2 Mb). These results extend previous studies by sublocalizing the regions of LOH and suggest that inactivation of one or more tumor suppressor genes located in these regions may be an important step in salivary gland carcinogenesis.

Blotting, Southern↗
PubMed1998

Breakdown of the inner and outer blood retinal barrier in streptozotocin-induced diabetes.

Using vitreous fluorophotometry and quantitative fluorescence microscopy the authors studied the permeability of the blood-retinal barrier (BRB) to fluorescein in control and in 8 days streptozotocin-induced diabetic rats. Vitreous fluorophotometry showed that fluorescein permeates BRB in control and in diabetic rats. However, in diabetic rats the permeability to fluorescein was significantly increased as compared to control rats. The vitreous penetration ratio (VPR) values for total and free fluorescein at 60 min, were higher for diabetic rats (231.2+/-12.9 min-1 for total fluorescein and 1299.24+/-58.0 min-1 for free fluorescein) than for control rats (95.5+/-3.5 min-1 for total fluorescein and 646.6+/-55. 0 min-1 for free fluorescein) (P<0.05). Quantitative confocal fluorescence microscopy confirmed these findings and identified the site of leakage across the BRB by comparing the relative importance of the fluorescein leakage across the outer and inner BRB. In control rats the fluorescence levels remained relatively low in the photoreceptor layer, next to the outer BRB but in the inner nuclear layer, next to the inner BRB reached values that were almost ten times higher. These results suggest that in retinas of control rats fluorescein penetrates predominantly through the inner BRB. In diabetic rats the fluorescence levels in the photoreceptor and in the inner nuclear layer were significantly increased as compared to the fluorescence levels in controls rats. Nevertheless, in the inner nuclear layer the fluorescence levels were also generally higher than the fluorescence levels at the photoreceptor layer. The rates of fluorescence levels between the inner nuclear layer and the photoreceptor layer were apparently 3:1, 60 min after the single intravenous injection of fluorescein. Also, the fluorescein penetration in the inner nuclear layer of the diabetic rats is higher than that observed in the inner nuclear layer of the control rats (P<0.001). These findings suggest that the permeability to fluorescein of both components of the BRB is increased 8 days after the induction of diabetes by streptozotocin and that the permeability of the retinal vasculature is preferentially affected.

Animals↗
PubMed1998

[Small abnormality of the middle ear--a genetically-induced defect?].

Conductive and sensorineural hearing losses are of genetic origin in 20% to 60% of cases. In general, genetic abnormalities are more often expressed as a sensorineural hearing loss than as a conductive hearing loss. At present several genes for sensorineural hearing loss have been isolated. The most common genetically transmitted forms for isolated conductive hearing losses are otosclerosis and small malformations of the ossicles. To date no genes responsible for these deformations have been isolated. We present a family with four siblings having conductive hearing losses caused by ossification of the stapedial tendon. This finding is suggestive of an autosomal recessive inheritance. The early diagnosis of an hereditary conductive hearing loss contains the possibility for permitting normal development of speech.

Adult↗
PubMed1998

A novel in situ method for the detection of deficient transglutaminase activity in the skin.

Autosomal recessive congenital ichthyoses are disorders of epidermal cornification, but are clinically and etiologically heterogeneous. Some cases, known as lamellar ichthyosis, are caused by mutations in the TGM1 gene encoding transglutaminase 1, which result in markedly diminished or lost enzyme activity and/or protein. In some cases, this enzyme is present but there is little detectable activity, and in other clinically similar cases, transglutaminase 1 levels appear to be normal. Since conventional enzyme assays and mutational analyses are tedious, we developed a novel assay for the rapid screening of transglutaminase 1 activity using covalent incorporation of biotinylated substrate peptides into skin cryostat sections. Coupled with immunohistochemical assays using transglutaminase 1 antibodies, our method allows rapid identification of those cases caused by alterations in this enzyme.

Chromosome Mapping↗
PubMed1998

A comparative investigation of FK506 and cyclosporin A in murine corneal transplantation.

BACKGROUND: Acute rejection is the cause of over 50% of transplant opacifications in some immunological high-risk groups. More potent immunomodulating substances must be found in order to allow extended or individualised therapeutic options for combating rejection. METHODS: Rats of the inbred strains Brown Norway and Lewis were used as donors and recipients, respectively. FK506 (Prograf) was administered intraperitoneally for 14 days in a dosage of 0.3 mg/kg bw, and cyclosporin A (CSA; Sandimmun) was administered, likewise for 14 days, in an intramuscular dosage of 10 mg/kg bw. The transplants were examined every 3rd day by slit-lamp microscopy. Every transplant was subjected to histological or immunohistological evaluation. RESULTS: The average transplant survival period in the allogeneic strain combination was 7.9 days (SEM = 1.1). Therapy with FK506 led to a statistically significant prolongation of transplant survival to 17.1 days (SEM = 1.5, P < 0.05). Therapy with CSA delayed transplant rejection to 21 days (SEM = 0.0, P < 0.05). No statistically significant difference was found between the two therapeutic regimens. There were no significant histomorphologic differences in rejected grafts in the FK506- and CSA-treated animals. CONCLUSIONS: In this study we have shown that FK506 is able to delay corneal allograft rejection at a much lower dosage than CSA without a higher incidence of side effects related to toxicity or overimmunosuppression.

Animals↗
PubMed1998

Genetic and immunohistochemical detection of mutations inactivating the keratinocyte transglutaminase in patients with lamellar ichthyosis.

Autosomal recessive lamellar ichthyosis is a clinically heterogeneous group of severe congenital keratinization disorders that is characterized by generalized hyperkeratosis and variable erythema. About half of the patients have mutations in the TGM1 gene, which encodes the keratinocyte transglutaminase. Linkage studies have shown that at least two further loci for autosomal recessive lamellar ichthyosis must exist. We present here two patients with lamellar ichthyosis caused by mutations in the TGM1 gene. The first patient is compound heterozygous for the novel missense mutation C53S and the splice mutation A3447G. The second patient, a child of consanguineous parents from Tunisia, is homozygous for the unknown nonsense mutation W263X. This is the first report of a mutation, C53S, that affects the region of the keratinocyte transglutaminase that is essential for anchorage of the enzyme to the plasma membrane. A novel, rapid in situ transglutaminase activity assay revealed the absence of keratinocyte transglutaminase activity in both patients. The mutations described are hence causative for the ichthyosis phenotype.

Adolescent↗
PubMed1998

Febrile seizures and generalized epilepsy associated with a mutation in the Na+-channel beta1 subunit gene SCN1B.

Febrile seizures affect approximately 3% of all children under six years of age and are by far the most common seizure disorder. A small proportion of children with febrile seizures later develop ongoing epilepsy with afebrile seizures. Segregation analysis suggests the majority of cases have complex inheritance but rare families show apparent autosomal dominant inheritance. Two putative loci have been mapped (FEB1 and FEB2), but specific genes have not yet been identified. We recently described a clinical subset, termed generalized epilepsy with febrile seizures plus (GEFS+), in which many family members have seizures with fever that may persist beyond six years of age or be associated with afebrile generalized seizures. We now report linkage, in another large GEFS+ family, to chromosome region 19q13.1 and identification of a mutation in the voltage-gated sodium (Na+)-channel beta1 subunit gene (SCN1B). The mutation changes a conserved cysteine residue disrupting a putative disulfide bridge which normally maintains an extracellular immunoglobulin-like fold. Co-expression of the mutant beta1 subunit with a brain Na+-channel alpha subunit in Xenopus laevis oocytes demonstrates that the mutation interferes with the ability of the subunit to modulate channel-gating kinetics consistent with a loss-of-function allele. This observation develops the theme that idiopathic epilepsies are a family of channelopathies and raises the possibility of involvement of other Na+-channel subunit genes in febrile seizures and generalized epilepsies with complex inheritance patterns.

Amino Acid Sequence↗
PubMed1998

[Latanoprost (Xalatan)-induced macular edema].

BACKGROUND: Latanoprost represents a new therapeutic option in the treatment of chronic open angle glaucoma. It has only recently been reported for the first time that latanoprost caused cystoid macular edema in pseudophakic patients. CASE REPORT: A 60-year-old pseudophakic patient who suffered from a 10-year history of glaucoma, revealed a cystoid macular edema on fluorescence angiography after 10 days of treatment with latanoprost. One week after cessation of latanoprost therapy the cystoid edema in fluorescence angiography had resolved and the vision improved from 0.4 to 0.8. CONCLUSIONS: With respect to this severe complication, latanoprost should be used with great care and in clear indications, particularly in patients with risk of blood-aqueous leakage e.g. pseudophakic patients.

Fluorescein Angiography↗
PubMed1998

[Mycophenolatemofetil in ocular immunological disorders. A survey of the literature with 3 case reports].

BACKGROUND: Up to now ophthalmologists have only a small number of substances in their therapeutic armamentarium for the treatment of ocular immunological disorders. These are very potent agents, and any rapidly proliferating cells are extremely sensitive to such agents, thus the possibility of severe side effects is great. Mycophenolatemofetil (MMF) has been shown to be effective in preventing acute graft rejection following clinical renal and cardiac transplantation with a low risk of adverse events. Likewise MMF was effective in the treatment of experimental immunological disorders. A review of literature was performed in Medline. CASE REPORTS: We report on the effective use of MMF in a patient with ocular cicatricial pemphigoid, the switch from Cyclosporin A (CSA) therapy to MMF therapy following high-risk keratoplasty due to CSA allergy and about the combination therapy (CSA/MMF) in a patient following high risk keratoplasty, in whom CSA monotherapy was not sufficient to prevent allograft rejection. CONCLUSIONS: In these three cases MMF has been shown to be a safe and effective agent for the treatment of ocular immunological disorders. Whether these beneficial casuistic experiences will hold true will be depended on the outcome of longterm studies underway.

Corneal Transplantation↗
PubMed1998

Gene localization for an autosomal dominant familial periodic fever to 12p13.

We report gene localization in a family with a benign autosomal dominant familial periodic fever (FPF) syndrome characterized by recurrent fever associated with abdominal pain. The clinical features are similar to the disorder previously described as familial Hibernian fever, and they differ from familial Mediterranean fever (FMF) in that FPF episodes usually do not respond to colchicine and FPF is not associated with amyloidosis. Frequent recombination with the marker D16S2622, <1 Mb from FMF, at 16p13.3, excluded allelism between these clinically similar conditions. Subsequently, a semiautomated genome search detected linkage of FMF to a cluster of markers at 12p13, with a multipoint LOD score of 6.14 at D12S356. If penetrance of 90% is assumed, the FPF gene maps to a 19-cM interval between D12S314 and D12S364; however, if complete penetrance is assumed, then FPF maps to a 9-cM region between D12S314 and D12S1695. This interval includes the dentatorubropallidoluysian atrophy locus, which, with FPF, gave a maximum two-point LOD score of 3.7 at a recombination fraction of 0. This is the first of the periodic-fever genes, other than FMF, to be mapped. Positional candidate genes may now be selected for mutation analysis to determine the molecular basis for FPF. Together with the recent identification of the defective gene in FMF, identification of a gene for FPF might provide new insights into the regulation of inflammatory responses.

Chromosome Mapping↗