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D F Schorderet

Publications and source records attributed to D F Schorderet.

At least 19 recordsLinked to original sources
PubMed2005

Keratoepithelin in secondary corneal amyloidosis.

BACKGROUND: Amyloid is found in several corneal dystrophies, including distinct lattice corneal dystrophies (LCD) and Avellino corneal dystrophy. Recently, point mutations in the transforming growth factor-beta-induced gene (TGFBI) encoding for keratoepithelin (KE) have been demonstrated in these corneal disease entities. We intended to investigate if KE was also a component of the rarely seen secondary corneal amyloid deposits. METHODS: Immunohistochemical staining with a polyclonal antibody against KE was performed on formalin-fixed paraffin-embedded tissue of five corneal buttons with secondary amyloid obtained after keratoplasty. Secondary amyloidosis was due to Fuchs endothelial dystrophy (FED) with bullous keratopathy and/or recurrent erosions in all cases. The diagnosis had been established by light microscopy using Congo red staining. Two cases of LCD type I served as positive controls and three corneas with FED and one with keratoconus without amyloid served as negative controls. RESULTS: All corneas with secondary amyloidosis as well as LCD type I revealed positive staining in the respective amyloid deposits. KE was localized in the subepithelial pannus and in the anterior stroma in the corneas with secondary amyloidosis. In the specimens with LCD type I it was distributed in the amyloid deposits located in the anterior and mid-stroma. Staining for KE showed a granular appearance in all cases. The intensity of staining was variable among the specimens. CONCLUSIONS: KE is found not only in primary amyloid deposits of hereditary corneal dystrophies, but also in secondary amyloidosis of the cornea of diverse ethiologies.

Adult↗
PubMed2005

Morphological, clinical and genetic aspects in a family with a novel LAMP-2 gene mutation (Danon disease).

A family with several cases of severe cardiomyopathy and moderate myopathy is described, affecting two brothers and their cousin as well as their mothers. One boy died of sudden cardiac arrest at 17 years of age. The two brothers were treated with an implantable defibrillator and their mother died suddenly at 40 years of age. Muscle biopsy in males showed vacuolar myopathy in two cases, and no abnormality on standard staining in the third case. Cardiac biopsies showed hypertrophic and vacuolated fibres. Complete absence of LAMP-2 was demonstrated by immunohistochemistry on the vacuolated skeletal and cardiac muscle, but also on the morphologically normal skeletal muscle. Sequencing of LAMP-2 gene showed a novel S157X mutation in exon 4. Danon disease is a rare and potentially lethal cause of hypertrophic cardiomyopathy. Diagnosis can be made by immunohistochemistry performed on cardiac or muscle biopsy, and confirmed by genetic analysis, which also allows for easy family screening and counselling.

Adolescent↗
PubMed2005

Clinical and immunopathological corneal phenotype in homozygotes for the BIGH3 R124H mutation.

A family was previously reported as suffering from severe granular dystrophy. The phenotypic picture suggested a mix of homozygous and heterozygous family members. Genetic analysis confirms the homozygousity in the patients most severely affected, but shows the disease state to be one of Avellino corneal dystrophy. The previous case reports are extended immunohistological staining using polyclonal antibodies raised against keratofepithelin. This genotype/phenotype correlation study is consistent with incomplete dominance.

Adolescent↗
PubMed2005

Lentiviral vector-mediated gene transfer in adult mouse photoreceptors is impaired by the presence of a physical barrier.

Gene transfer offers a substantial promise for the therapy of degenerative ocular diseases. Lentiviral vectors have the ability to efficiently transduce murine photoreceptors during the first days of life, but they are poorly effective on photoreceptors during adulthood. Here, we studied whether a physical barrier was responsible for this impairment. Previous studies have described the capacity of enzymes, such as chondroitinase ABC and neuraminidase X, to modify the structure of the interphotoreceptor matrix (IPM) when subretinally injected. Considering the IPM as a physical barrier that may decrease photoreceptor transduction, we injected different enzymes into the subretinal space of the adult mouse simultaneously with the lentiviral vector preparation, to increase viral transduction by fragilizing the IPM. Subretinal injection of neuraminidase X and chondroitinase ABC induces modifications in the IPM by, respectively, revealing or decreasing peanut agglutinin sites on photoreceptors. The simultaneous subretinal injection of neuraminidase X with a lentiviral vector driving the expression of a reporter gene in the photoreceptors increases the number of transduced cells significantly (around five-fold). After the enzyme treatment, the diffusion of the vector between the pigmented epithelium and the photoreceptors appears to facilitate the lentiviral vector transduction. Such approach targeting the IPM may help to design new strategies to improve gene delivery into the adult photoreceptors.

Animals↗
PubMed2005

[Optical coherence tomography in Malattia Leventinese].

BACKGROUND: Malattia Leventinese (ML) is a genetically homogeneous macular dystrophy with an autosomal dominant mode of inheritance. Ophthalmoscopically it is recognisable by a radial pattern of drusen-like deposits in the macula and by parapapillary deposits, named Forni's verrucosities. The aim of this study is to describe optical coherence tomographic (OCT) findings and to compare them with histological data. PATIENTS AND METHODS: Six patients underwent ophthalmological examination, angiography and OCT. Diagnosis was confirmed by genetic analysis of the R345W mutation. A histopathological study of an ML donor eye was performed. RESULTS: OCT revealed a diffuse RPE-choriocapillaris thickening with nodular features in the macular and parapapillary areas. The protrusions reached as far as the outer nuclear layer. CONCLUSIONS: OCT is a non-invasive technique that provides a cross-sectional picture of the retina comparable to a histological section. In ML, OCT revealed a diffuse alteration of the RPE-Bruch's membrane complex. The macular and parapapillary nodular lesions are the tomographic equivalents of drusen and Forni's verrucosities.

Adolescent↗
PubMed2004

Circadian regulation of islet genes involved in insulin production and secretion.

Both transcription factors albumin site d-binding protein (DBP) and thyrotroph embryonic factor (TEF) are elements of the "cell-clock". Their circadian accumulation in suprachiasmatic nucleus (SCN) and peripheral tissues such as liver, kidney and lung is thought to participate in controlling circadian regulation of downstream genes. TEF and DBP control elements have never been investigated in the insulin-secreting cells, but impairment of the circadian rhythm of the beta-cells might be involved in the development of diabetic state as type 2 diabetics have lost daily temporal variations of insulin secretion. We investigated the expression pattern of TEF and DBP in insulin-secreting cells. TEF and DBP transcripts are expressed at extremely high levels in human pancreatic islets compared to other tissues, suggesting a potentially important circadian regulation of these cells. Both TEF and DPB accumulate in a circadian way in insulin-secreting cells after a serum shock known to restore circadian rhythms in cultured cells. In addition, the expression of islet-specific genes involved in glucose sensing (glucose transporter 2 (Glut2), glucokinase), insulin production (insulin) and secretion (migration inhibitory factor (MIF), somatostatin and syntaxin 1A) were modulated in the same daily rhythm as well. The circadian deregulation of these genes could therefore participate in the diabetic state development.

Antigens, Surface↗
PubMed2004

[Early recurrence of Groenouw type I corneal dystrophy after phototherapeutic keratectomy. Molecular biology study suggests epithelial genesis].

PURPOSE: Granular corneal dystrophy Groenouw type 1 (GGI) is a rare autosomal dominant disease caused by allelic mutations of the BIGH3 gene. The specific phenotype is characterized by granular opacities (white, sharply demarcated spots resembling bread crumbs) in corneal stroma, which cause recurrent corneal erosions and blurred vision. Phototherapeutic keratectomy (PTK) is an effective procedure that improves visual acuity, but recurrences are unavoidable. Though GGI deposits are well described, their origin is not completely known. The production of mutated keratoepithelin protein (a product of the BIGH3 gene) is the first step necessary for deposits to appear. Molecular biology experiments were conducted to determine the role of corneal cell types in the genesis of early recurrent deposits of post-PTK GGI. METHODS: Tissue specimens from a patient undergoing penetrating keratoplasty for recurrence of GGI (12 months after PTK) and five normal corneas were examined by hybridization in situ and immunohistology to study the expression of BIGH3 and location of keratoepithelin. RESULTS: Only one healthy cornea expressed BIGH3 mainly in the epithelium and less in keratinocytes and endothelial cells. In the GGI corneas, BIGH3 was highly expressed in the modified, hyperplastic epithelium. The keratoepithelin was accumulated under the epithelium where deposits were formed. CONCLUSION: This observation confirms that corneal epithelium is the main producer of mutated keratoepithelin on the cellular scale and thus constitutes the principal source of dystrophic deposit formation during recurrence.

Adult↗
PubMed2003

Activity analysis of housekeeping promoters using self-inactivating lentiviral vector delivery into the mouse retina.

For most retinal degeneration disorders, no efficient treatment exists to preserve photoreceptors (PRs) and, consequently, to maintain vision. Gene transfer appears to be a promising approach to prevent PR loss. In order to design adequate vectors to target specific retinal cell types, we have analyzed the expression pattern of three different promoters (mouse phosphoglycerate kinase 1 (PGK), elongation factor-1 (EFS), rhodopsin (Rho)) in newborn and adult DBA/2 mice retinas using self-inactivating lentiviral vectors. At 7 days after intraocular injection and in optimal conditions, cell transduction was observed up to 1.5 mm from the injection site. PGK promoter expression was predominant in the retinal pigment epithelium (RPE), especially in adult mice, whereas the EFS promoter allowed a broad expression in the retina. Finally, as expected, the Rho promoter was specifically expressed in PRs. Differences in the cell types transduced and in transduction efficiency were observed between newborn and adult injected eyes emphasizing the importance of such basic studies for further gene therapy approaches as well as for understanding the transcriptional changes during retinal maturation. Thus, for future attempts to slow or rescue retinal degeneration by lentiviral delivery, PGK and EFS are more suitable to control the expression of a supporting secreted factor, PGK being mainly expressed in RPE and EFS in different cell types throughout the entire retina, whereas Rho should allow to specifically deliver the therapeutic gene to PRs.

Animals↗
PubMed2002

Use of denaturing HPLC and automated sequencing to screen the VMD2 gene for mutations associated with Best's vitelliform macular dystrophy.

We identified three novel VMD2 mutations in patients with Best's macular dystrophy. DHPLC analysis of the 11 VMD2 exons revealed abnormal profiles in exon 8. Direct sequencing showed that these abnormal profiles were due to monoallelic transitions and transversions. We also found three polymorphic sequence changes that have been reported previously and annotated to an online database (http://www.uni-wuerzburg.de/humangenetics/vmd2.html).

Bestrophins↗
PubMed2002

Partial trisomy 20q in a newborn with dextrocardia.

A female newborn is reported with dextrocardia and a partial trisomy 20q, derived from a t(2;20) paternal translocation. The most discriminating findings of the condition include brachycephaly, bulging forehead, deep set eyes, short nose, large ears, dimpled chin, short neck and a heart defect. Previously reported patients with this rare chromosomal anomaly are reviewed.

Chromosomes, Human, Pair 20↗
PubMed2001

Missense mutations in COL8A2, the gene encoding the alpha2 chain of type VIII collagen, cause two forms of corneal endothelial dystrophy.

Corneal clarity is maintained by its endothelium, which functions abnormally in the endothelial dystrophies, leading to corneal opacification. This group of conditions includes Fuchs' endothelial dystrophy of the cornea (FECD), one of the commonest indications for corneal transplantation performed in developed countries, posterior polymorphous dystrophy (PPCD) and the congenital hereditary endothelial dystrophies (CHED). A genome-wide search of a three-generation family with early-onset FECD demonstrated significant linkage with D1S2830 (Z(max) = 3.72, theta = 0.0). Refinement of the critical region defined a 6-7 cM interval of chromosome 1p34.3-p32 within which lies the COL8A2 gene. This encodes the 703 amino acid alpha2 chain of type VIII collagen, a short-chain collagen which is a component of endothelial basement membranes and which represented a strong candidate gene. Analysis of its coding sequence defined a missense mutation (gln455lys) within the triple helical domain of the protein in this family. Mutation analysis in patients with FECD and PPCD demonstrated further missense substitutions in familial and sporadic cases of FECD as well as in a single family with PPCD. This is the first description of the molecular basis of any of the corneal endothelial dystrophies or of mutations in type VIII collagen in association with human disease. This suggests that the underlying pathogenesis of FECD and PPCD may be related to disturbance of the role of type VIII collagen in influencing the terminal differentiation of the neural crest derived corneal endothelial cell.

Amino Acid Sequence↗
PubMed2001

Rearrangements of minisatellites in the human telomerase reverse transcriptase gene are not correlated with its expression in colon carcinomas.

Telomerase activation is crucial in human carcinogenesis. The limiting component of telomerase, the catalytic subunit (hTERT), is undetectable in normal somatic cells but present in most tumor cells, including the earliest stages of colon carcinoma. The mechanisms involved in the differential expression in normal and tumor cells are not understood. In normal cells hTERT expression is shut down by a repressor, and upregulation could be a consequence of cis-acting changes in the hTERT gene, making it resistant to repression. We have identified a polymorphic and a monomorphic minisatellite in the second intron of the hTERT gene, and polymorphic one in intron 6. The polymorphic minisatellite in intron 2 contains binding sites for c-Myc, which has been shown to upregulate hTERT transcription. Screening colon carcinoma DNAs for rearrangements of hTERT minisatellites we detected no changes in 33 samples from tumors, most of which express hTERT. This indicates that size rearrangements of the hTERT minisatellites are not required for telomerase expression in colon carcinomas. Minor changes and one LOH were seen in five tumors.

Base Sequence↗
PubMed2001

A progressive autosomal recessive cataract locus maps to chromosome 9q13-q22.

Cataracts are the leading cause of blindness in most countries. Although most hereditary cases appear to follow an autosomal dominant pattern of inheritance, autosomal recessive inheritance has been clearly documented and is probably underrecognized. We studied a large family-from a relatively isolated geographic region-whose members were affected by autosomal recessive adult-onset pulverulent cataracts. We mapped the disease locus to a 14-cM interval at a novel disease locus, 9q13-q22 (between markers D9S1123 and D9S257), with a LOD score of 4.7. The study of this progressive and age-related cataract phenotype may provide insight into the cause of the more common sporadic form of age-related cataracts.

Adult↗
PubMed2001

Variation of codons 1961 and 2177 of the Stargardt disease gene is not associated with age-related macular degeneration.

OBJECTIVES: To investigate the role of 2 specific alleles of the Stargardt disease gene (ABCA4) in the pathogenesis of age-related macular degeneration (AMD). Secondary objectives were to investigate differences in frequency of the G1961E allele in selected ethnic groups as well as to examine the segregation of both G1961E and D2177N alleles in 5 multiplex families with AMD. METHODS: Five hundred forty-four patients with AMD and 689 controls were ascertained from 3 continents. Blood samples from 62 normal individuals of Somalian ancestry were also obtained. Participants were screened for the presence of these ABCA4 alleles with a combination of restriction digestion and single-strand conformation polymorphism analysis of polymerase chain reaction amplification products. Detected alleles were confirmed by DNA sequencing. The number of subjects exhibiting the G1961E or D2177N variants were compared between AMD and control groups using a 2-tailed Fisher exact test. RESULTS: There was no significant difference (P >.1) in the frequency of the G1961E and D2177N alleles in patients with AMD (2.2%) vs controls (1.0%). In contrast, there was a significant difference (P< .001) in the frequency of the G1961E alleles between normal individuals of Somali ancestry (11.3%) and normal individuals from other populations (0.4%). There was no evidence of cosegregation of these alleles and the AMD phenotype in the 5 multiplex families with AMD examined. These two ABCA4 alleles were slightly more frequent in patients with AMD with choroidal neovascularization (2.7%) than those without this complication (2.5%). CONCLUSIONS: Somali ancestry is more than 100 times more strongly associated with presence of the G1961E allele than the AMD phenotype. This study did not find any statistically significant evidence for involvement of the G1961E or D2177N alleles of the ABCA4 gene in AMD. CLINICAL RELEVANCE: The ABCA4 gene is definitively involved in the pathogenesis of Stargardt disease and some cases of photoreceptor degeneration. However, it does not seem to be involved in a statistically significant fraction of AMD cases.

ATP-Binding Cassette Transporters↗
PubMed2001

Molecular and clinical characteristics in 32 families affected with familial adenomatous polyposis.

Germ-line mutations in the 5' half of the Adenomatous Polyposis Coli (APC) gene are found in about 80% of the patients affected with familial adenomatous polyposis (FAP). The vast majority of these are nonsense or frameshift mutations which result in the loss of the carboxyl terminus of the APC protein. Using an in vivo assay in yeast, we have identified pathogenic germ-line mutations in 26 of 32 (81%) unrelated Swiss families affected with FAP. Nine mutations were novel and eight families were shown to harbor two recurrent mutations. Correlations were attempted between the location of APC germ-line mutations and clinical manifestations of the disease.

Adenomatous Polyposis Coli↗
PubMed2001

Identification of novel VMD2 gene mutations in patients with best vitelliform macular dystrophy.

ABSTRACT We report five novel VMD2 mutations in Best's macular dystrophy patients (S16F, I73N, R92H, V235L, and N296S). An SSCP analysis of the VMD2 11 exons revealed electrophoretic mobility shifts exclusively in exons 2, 3, 4, 6 and 8. Direct sequencing indicated that these shifts are caused by mono-allelic transition in exons 2, 4, 6, 8 and transversion in exons 3 and 6. Five novel "silent" polymorphisms are also reported: 213T>C, 323C>A, 1514A>G, 1661C>T, and 1712T>C. Hum Mutat 17:235, 2001.

Base Sequence↗
PubMed2001

A characteristic EEG pattern in 4p-syndrome: case report and review of the literature.

UNLABELLED: Deletions on the short arm of chromosome 4 cause Wolf-Hirschhorn syndrome (WHS) and Pitt-Rogers-Danks syndrome (PRDS). WHS is associated with severe growth and mental retardation, microcephaly, a characteristic facies and congenital malformations. The PRDS phenotype is similar to WHS but generally less severe. Seizures occur in the majority of WHS and PRDS patients. Sgrò et al. [17] described a stereotypic electroclinical pattern in four unrelated WHS patients, consisting of intermittent bursts of 2-3 Hz high voltage slow waves with spike wave activity in the parietal areas during drowsiness and sleep associated with myoclonic jerks. We report a patient with PRDS and the typical EEG pattern and review 14 WHS patients with similar EEG findings reported in the literature. CONCLUSION: Awareness and recognition of the characteristic electroclinical findings in Wolf-Hirschhorn syndrome and Pitt-Rogers-Danks syndrome might help in the early diagnosis of such patients.

Abnormalities, Multiple↗