Biomedical subjects
A Reis
Publications and source records attributed to A Reis.
Leukemic infiltrations of the peritoneum at diagnosis and the breast at relapse in a child with acute B-cell lymphoblastic leukemia.
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Hereditary isolated renal magnesium loss maps to chromosome 11q23.
Hypomagnesemia due to isolated renal magnesium loss has previously been demonstrated in two presumably unrelated Dutch families with autosomal dominant mode of inheritance. Patients with magnesium deficiency may suffer from tetany and convulsions, but the patients with hereditary renal magnesium wasting can also be clinically nonsymptomatic. In a genomewide linkage study, we first excluded a possible candidate region, on chromosome 9q, that encompasses the gene for intestinal hypomagnesemia with secondary hypocalcemia and, subsequently, found linkage to markers on chromosome 11q23. Detailed haplotype analyses identified a common haplotype segregating in both families, suggesting both their relationship through a common ancestor and the existence of a single, hypomagnesemia-causing mutation within them. The maximum two-point LOD score (Zmax) was found for marker D11S4127 (Zmax=6.41 at a recombination fraction of. 00), whereas a multipoint analysis gave a Zmax of 8.24 between markers D11S4142 and D11S4171. Key recombination events define a 5. 6-cM region between these two markers on chromosome 11q23. We conclude that this region encompasses a gene, involved in renal magnesium handling, that is mutated in our patients and is different from the gene involved in intestinal magnesium handling.
Limb mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other Hand/Foot anomalies maps to human chromosome 3q27.
We report on a large Dutch family with a syndrome characterized by severe hand and/or foot anomalies, and hypoplasia/aplasia of the mammary gland and nipple. Less frequent findings include lacrimal-duct atresia, nail dysplasia, hypohydrosis, hypodontia, and cleft palate with or without bifid uvula. This combination of symptoms has not been reported previously, although there is overlap with the ulnar mammary syndrome (UMS) and with ectrodactyly, ectodermal dysplasia, and clefting syndrome. Allelism with UMS and other related syndromes was excluded by linkage studies with markers from the relevant chromosomal regions. A genomewide screening with polymorphic markers allowed the localization of the genetic defect to the subtelomeric region of chromosome 3q. Haplotype analysis reduced the critical region to a 3-cM interval of chromosome 3q27. This chromosomal segment has not been implicated previously in disorders with defective development of limbs and/or mammary tissue. Therefore, we propose to call this apparently new disorder "limb mammary syndrome" (LMS). The SOX2 gene at 3q27 might be considered an excellent candidate gene for LMS because the corresponding protein stimulates expression of FGF4, an important signaling molecule during limb outgrowth and development. However, no mutations were found in the SOX2 open reading frame, thus excluding its involvement in LMS.
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.
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.
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.
[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.
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.
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.
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.
Mycophenolate mofetil and FK506: two novel immunosuppressants in murine corneal transplantation.
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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.
[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.
[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.
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.
Genotype/phenotype correlation in autosomal recessive lamellar ichthyosis.
Autosomal recessive lamellar ichthyosis is a severe congenital disorder of keratinization, characterized by variable erythema of the whole body surface and by different scaling patterns. Recently, mutations have been identified in patients with lamellar ichthyosis in the TGM1 gene coding for keratinocyte transglutaminase, and a second locus has been mapped to chromosome 2. We have now analyzed the genotype/phenotype correlation in a total of 14 families with lamellar ichthyosis. Linkage analyses using microsatellites in the region of the TGM1 gene confirmed genetic heterogeneity. In patients not linked to the TGM1 gene, the second region identified on chromosome 2 and a further candidate region on chromosome 20 were excluded, confirming as well the existence of at least three loci for lamellar ichthyosis. Sequence analyses of the TGM1 gene in families compatible with linkage to this locus revealed seven different missense mutations, five of these unpublished so far, and one splice mutation. No genotype/phenotype correlation for mutations in the TGM1 gene was found in this group of patients, which included two unrelated patients homozygous for the same mutation. Similarly, no clear difference in the clinical picture was seen between patients with TGM1 mutations and those unlinked to the TGM1 locus. Comparison of genetic and clinical classifications for patients with lamellar ichthyosis shows no consistency and thus indicates that clinical criteria currently in use cannot discriminate between the molecularly different forms of the disease.
Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: implications for imprint-switch models, genetic counseling, and prenatal diagnosis.
The Prader-Willi syndrome (PWS) and the Angelman syndrome (AS) are caused by the loss of function of imprinted genes in proximal 15q. In approximately 2%-4% of patients, this loss of function is due to an imprinting defect. In some cases, the imprinting defect is the result of a parental imprint-switch failure caused by a microdeletion of the imprinting center (IC). Here we describe the molecular analysis of 13 PWS patients and 17 AS patients who have an imprinting defect but no IC deletion. Heteroduplex and partial sequence analysis did not reveal any point mutations of the known IC elements, either. Interestingly, all of these patients represent sporadic cases, and some share the paternal (PWS) or the maternal (AS) 15q11-q13 haplotype with an unaffected sib. In each of five PWS patients informative for the grandparental origin of the incorrectly imprinted chromosome region and four cases described elsewhere, the maternally imprinted paternal chromosome region was inherited from the paternal grandmother. This suggests that the grandmaternal imprint was not erased in the father's germ line. In seven informative AS patients reported here and in three previously reported patients, the paternally imprinted maternal chromosome region was inherited from either the maternal grandfather or the maternal grandmother. The latter finding is not compatible with an imprint-switch failure, but it suggests that a paternal imprint developed either in the maternal germ line or postzygotically. We conclude (1) that the incorrect imprint in non-IC-deletion cases is the result of a spontaneous prezygotic or postzygotic error, (2) that these cases have a low recurrence risk, and (3) that the paternal imprint may be the default imprint.