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Biomedical subjects

P Tsipouras

Publications and source records attributed to P Tsipouras.

At least 19 recordsLinked to original sources
PubMed1997

Chronic pain is a manifestation of the Ehlers-Danlos syndrome.

The Ehlers-Danlos syndrome (EDS) is a group of heritable systemic disorders of connective tissue manifesting joint hypermobility, skin extensibility, and tissue fragility. Although the presence of pain has been documented in the various types of the EDS, its natural history, distribution, and management have not been defined. We conducted a structured interview in 51 individuals affected with different types of EDS. Affected individuals reported chronic pain of early onset involving most frequently the shoulders, hands, and knees. Pain was generally refractory to a variety of pharmacologic and physical interventions. Chronic pain is a common manifestation of EDS.

Adaptation, Psychological↗
PubMed1997

Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1.

Chondrodysplasia Grebe type (CGT) is an autosomal recessive disorder characterized by severe limb shortening and dysmorphogenesis. We have identified a causative point mutation in the gene encoding the bone morphogenetic protein (BMP)-like molecule, cartilage-derived morphogenetic protein-1 (CDMP-1). The mutation substitutes a tyrosine for the first of seven highly conserved cysteine residues in the mature active domain of the protein. We demonstrate that the mutation results in a protein that is not secreted and is inactive in vitro. It produces a dominant negative effect by preventing the secretion of other, related BMP family members. We present evidence that this may occur through the formation of heterodimers. The mutation and its proposed mechanism of action provide the first human genetic indication that composite expression patterns of different BMPs dictate limb and digit morphogenesis.

Amino Acid Sequence↗
PubMed1996

A split hand-split foot (SHFM3) gene is located at 10q24-->25.

The split hand-split foot (SHSF) malformation affects the central rays of the upper and lower limbs. It presents either as an isolated defect or in association with other skeletal or non-skeletal abnormalities. An autosomal SHSF locus (SHFM1) was previously mapped to 7q22.1. We report the mapping of a second autosomal SHSF locus to 10q24-->25. A panel of families was tested with 17 marker loci mapped to the 10q24-->25 region. Maximum lod scores of 3.73, 4.33 and 4.33 at a recombination fraction of zero were obtained for the loci D10S198, PAX2 and D10S1239, respectively. An 19 cM critical region could be defined by haplotype analysis and several genes with a potential role in limb morphogenesis are located in this region. Heterogeneity testing indicates the existence of at least one additional autosomal SHSF locus.

Abnormalities, Multiple↗
PubMed1996

Delivery of a hammerhead ribozyme specifically down-regulates the production of fibrillin-1 by cultured dermal fibroblasts.

The hammerhead ribozyme is a small catalytic RNA molecule. Potential hammerhead ribozymes that possess a catalytic domain and flanking sequence complementary to a target mRNA can cleave in trans at a putative cleavage site within the target molecule. We have investigated the potential of hammerhead ribozymes to down-regulate the product of the fibrillin-1 gene (FBN1). Fibrillin is a 347 kDa glycoprotein that is a major constituent of the elastin-associated microfibrils. Mutations in the FBN1 gene are responsible for Marfan syndrome (MFS), a common systemic disorder of the connective tissue. Many FBN1 mutations responsible for MFS appear to act in a dominant-negative fashion, raising the possibility that reduction of the amount of product from the mutant FBN1 allele might be a valid therapeutic approach for MFS. A trans-acting hammerhead ribozyme (FBN1-RZ1) targeted to the 5' end of the human FBN1 mRNA has been designed and synthesized, and shown to cleave its target efficiently in vitro. FBN1-RZ1 cleavage is magnesium dependent and efficient at both 37 and 50 degrees C. Delivery of the FBN1-RZ1 ribozyme into cultured dermal fibroblasts, by receptor-mediated endocytosis of a ribozyme-transferrin-polylysine complex, specifically reduces both cellular FBN1 mRNA and the deposition of fibrillin in the extracellular matrix. These results suggest that the use of hammerhead ribozymes is a valid approach to the study of fibrillin gene expression and possibly to the development of a therapeutic approach to MFS.

Base Sequence↗
PubMed1996

Preimplantation genetic testing for Marfan syndrome.

Marfan syndrome (MFS) is an autosomal dominant disease that affects the skeletal, ocular and cardiovascular systems. Defects in the gene that codes for fibrillin (FBN-1) are responsible for MFS. Here we report the world's first use of preimplantation genetic testing (PGT) to achieve a clinical pregnancy and live birth of a baby free of a Marfan mutation. One or two blastomeres from each embryo were tested for a CA repeat within the FBN-1 gene. The prospective mother is homozygous for the CA repeat (2/2) and has two normal copies of the FBN-1 gene, while the prospective father is heterozygous for the CA repeat (1/2), and is affected with the Marfan syndrome. In the father's family, allele 2 segregates with the mutated FBN-1 gene. For PGT, any embryo diagnosed as heterozygous for the CA repeat (1/2) would be presumed to have inherited normal FBN-1 genes from the father and the mother and be unaffected. One in-vitro fertilization (IVF) cycle yielded 12 embryos for preimplantation testing; six of the embryos were heterozygous for the CA repeat (1/2) and presumed to be free of the Marfan mutation. Five of the six embryos were subsequently transferred into the uterus. The fetus was tested by chorionic villus sampling and found to be free of the Marfan mutation by the same linkage analysis, had a normal fetal echocardiogram, and was normal at birth.

Adult↗
PubMed1995

Molecular cloning of the microfibrillar protein MFAP3 and assignment of the gene to human chromosome 5q32-q33.2.

Microfibrils having a diameter of 10-12 nm, found either in association with elastin or independently, are an important component of the extracellular matrix of many tissues, but characterization of these microfibrils is incomplete. To further our understanding of the gene structure of proteins composing the microfibrils and to identify their chromosomal location, we have cloned and characterized another microfibril protein, designated microfibril-associated protein-3 (MFAP3). The human gene encoding MFAP3 has a very simple structure, containing only two translated exons encoding a protein of 362 amino acids. Monospecific antibodies prepared against the recombinantly expressed protein reacted with the microfibrils found in ocular zonules. MFAP3 does not appear to share homology with any other known protein. The gene was found to be located on chromosome 5q32-q33.2, near the locus 5q21-q31 reported for the fibrillin gene, FBN2, which has been linked to congenital contractural arachnodactyly. MFAP3 is a candidate gene for heritable diseases affecting microfibrils.

Amino Acid Sequence↗
PubMed1995

Life expectancy in the Marfan syndrome.

Data reported in 1972 indicated that lifespan in patients with the Marfan syndrome is markedly shortened, and that most deaths are cardiovascular. This study was performed to determine whether survival in the Marfan syndrome has changed since 1972, and to discern whether treatment (medical or surgical) has altered prognosis. Survival curves were generated on 417 patients from 4 referral centers, with a definite diagnosis of the Marfan syndrome. Birth date, age at death, cardiovascular surgery, or treatment with beta blockers, or any combination of these, were included in the analysis. Forty-seven of 417 patients died. Mean age at death (41 +/- 18 years) was significantly increased compared with age in 1972 (32 +/- 16 years, p = 0.0023). Median (50%) cumulative probability of survival in 1993 was 72 years compared with 48 years in 1972. Of 112 surgically treated patients, 10-year probability of survival was 70%. Patients undergoing surgery after 1980 enjoyed significantly increased survival than patients who had undergone operation before 1980 (p = 0.008). In conclusion, life expectancy for patients with the Marfan syndrome has increased > 25% since 1972. Reasons for this dramatic increase may include (1) an overall improvement in population life expectancy, (2) benefits arising from cardiovascular surgery, and (3) greater proportion of milder cases due to increased frequency of diagnosis. Medical therapy (including beta blockers) was also associated with an increase in probable survival.

Adult↗
PubMed1995

A common FGFR3 gene mutation is present in achondroplasia but not in hypochondroplasia.

Achondroplasia is the most common type of genetic dwarfism. It is characterized by disproportionate short stature and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. Recent studies mapped the achondroplasia gene on chromosome region 4p16.3 and identified a common mutation in the gene encoding the fibroblast growth factor receptor 3 (FGFR3). In an analysis of 19 achondroplasia families from a variety of ethnic backgrounds we confirmed the presence of the G380R mutation in 21 of 23 achondroplasia chromosomes studied. In contrast, the G380R mutation was not found in any of the 8 hypochondroplasia chromosomes studied. Furthermore, linkage studies in a 3-generation family with hypochondroplasia show discordant segregation with markers in the 4p16.3 region suggesting that at least some cases of hypochondroplasia are caused by mutations in a gene other than FGFR3.

Achondroplasia↗
PubMed1995

Family history of severe cardiovascular disease in Marfan syndrome is associated with increased aortic diameter and decreased survival.

OBJECTIVES: We attempted to determine whether a family history of severe cardiovascular disease in patients with the Marfan syndrome is associated with increased aortic dilation or decreased survival, or both. BACKGROUND: The prognostic importance of a family history of severe cardiovascular disease in patients with the Marfan syndrome has been incompletely examined. We hypothesized that such a family history would correlate with increased aortic dilation and would be associated with decreased survival. METHODS: One hundred eight affected patients and 48 unaffected family members from 33 multigenerational families with the Marfan syndrome underwent echocardiographic measurement of the aortic root, arch and mid-abdominal aorta. Date of birth and age at death ascertained from family pedigrees were used to perform life table analysis and estimate survival. RESULTS: Aortic root and arch diameters were significantly greater in patients with a family history of severe cardiovascular disease than in patients without such a family history. Of subjects in the highest quartile for aortic size, > 80% had such a family history in contrast to < 10% of those in the lowest quartile (chi-square 57.37, p < 0.00001). Mean age at death and cumulative probability of survival were significantly lower in patients with such a family history. CONCLUSIONS: Among patients with the Marfan syndrome, aortic dilation is greater and life expectancy shorter in those with a family history of severe cardiovascular manifestations. These data suggest that such a family history is an important risk factor for cardiovascular events in patients with the Marfan syndrome.

Adult↗
PubMed1995

A common FGFR3 gene mutation in hypochondroplasia.

Hypochondroplasia is a genetic disorder of disproportionate short stature. Linkage analysis provisionally placed hypochondroplasia in the chromosome 4p 16.3 region, a location to which the FGFR3 gene has been mapped. The genotyping of a three-generation family showed no recombinants between the hypochondroplasia phenotype and three highly polymorphic markers flanking the FGFR3 gene. Mutation analysis was performed by RT-PCR and direct sequencing. Primers covering most of the coding sequence of the FGFR3 gene were used for RT-PCR of FGFR3 mRNA and PCR amplification of genomic DNA. A C-->A transversion was detected in nucleotide 1659 predicting an N540K substitution in exon 11 which encodes part of the TK1 domain. The same mutation was found in an individual suspected to be an achondroplasia/hypochondroplasia compound phenotype and affected individuals from three other unrelated families. A second mutation, a C-->G transversion, also in nucleotide 1659 was detected in all affected individuals of another family. The latter also predicts an N540K substitution. These findings establish that a common mutation in the FGFR3 gene underlies hypochondroplasia.

Amino Acid Sequence↗
PubMed1994

Psychosocial functioning in the Ehlers-Danlos syndrome.

Ehlers-Danlos Syndrome (EDS) is a group of related genetic disorders of connective tissue presenting with joint hypermobility, skin extensibility, and tissue fragility. Although the pathophysiology of EDS is increasingly understood, the psychosocial effects of having EDS have not been examined. We psychologically tested and interviewed 41 adults and 7 children with EDS. Anxiety, depression, anger, and interpersonal concerns were significantly elevated, varying from one-quarter to one-third of patients; over 70% had a history of some mental health care use. Psychological difficulties appear to result from chronic pain and disability, ostracism or avoidance of relationships and social activities, sexual difficulties and reproductive concerns, and frustration with the medical system. Specific types of EDS (e.g., EDS Type I) are associated with greater pain and psychological distress. Psychological intervention, prescribed with the recognition that psychiatric features are secondary to EDS, is recommended for some patients.

Adolescent↗
PubMed1994

The gene for achondroplasia maps to the telomeric region of chromosome 4p.

Achondroplasia is the most common type of genetic dwarfism. It is characterized by disproportionate short stature and other skeletal anomalies resulting from a defect in the maturation of the chondrocytes in the growth plate of the cartilage. We have now mapped the achondroplasia gene near the telomere of the short arm of chromosome 4 (4p16.3), by family linkage studies using 14 pedigrees. A positive lod score of z = 3.35 with no recombinants was obtained with an intragenic marker for IDUA. This localization will facilitate the positional cloning of the disease gene.

Achondroplasia↗
PubMed1993

Limb-girdle muscular dystrophy is closely linked to the fibrillin locus on chromosome 15.

Limb-girdle Muscular Dystrophy (LGMD) is a rare form of muscular dystrophy inherited as an autosomal recessive trait. The LGMD locus was recently mapped to chromosome 15. We tested the hypothesis that fibrillin is a candidate in the etiology of the disorder by genetic linkage analysis. A large Amish kindred segregating the disorder was genotyped for two markers specific for the fibrillin gene on chromosome 15. A total of 105 individuals were genotyped and a maximum LOD score of Z = 9. 135 at theta = 0.04 was obtained. Our results confirmed the mapping of the LGMD on chromosome 15 and excluded fibrillin as a candidate molecule. These data will be useful in the construction of a fine map of the region surrounding the LGMD locus, a prerequisite for the cloning of the LGMD gene.

Base Sequence↗
PubMed1993

Prenatal diagnosis and a donor splice site mutation in fibrillin in a family with Marfan syndrome.

The Marfan syndrome, an autosomal dominant connective tissue disorder, is manifested by abnormalities in the cardiovascular, skeletal, and ocular systems. Recently, fibrillin, an elastin-associated microfibrillar glycoprotein, has been linked to the Marfan syndrome, and fibrillin mutations in affected individuals have been documented. In this study, genetic linkage analysis with fibrillin specific markers was used to establish the prenatal diagnosis in an 11-wk-gestation fetus in a four-generation Marfan kindred. At birth, skeletal changes suggestive of the Marfan syndrome were observed. Reverse transcription-PCR amplification of the fibrillin gene mRNA detected a deletion of 123 bp in one allele in affected relatives. This deletion corresponds to an exon encoding an epidermal growth factor-like motif. Examination of genomic DNA showed a G-->C transversion at the +1 consensus donor splice site.

Adult↗
PubMed1993

Marfan syndrome: genetic basis and clinical manifestations.

Marfan syndrome is a systemic heritable disorder of connective tissue. The manifestations of the disorder are primarily from the musculoskeletal, cardiovascular, and ocular systems. Marfan syndrome is caused by mutations in the fibrillin gene located on chromosome 15.

Fibrillins↗
PubMed1992

Genetic linkage of the Marfan syndrome, ectopia lentis, and congenital contractural arachnodactyly to the fibrillin genes on chromosomes 15 and 5. The International Marfan Syndrome Collaborative Study.

BACKGROUND: The large glycoprotein fibrillin is a structural component of elastin-containing microfibrils found in many tissues. The Marfan syndrome has been linked to the fibrillin gene on chromosome 15, but congenital contractural arachnodactyly, which shares some of the physical features of the syndrome, has been linked to the fibrillin gene on chromosome 5. METHODS: Using specific markers for the fibrillin genes, we performed genetic linkage analysis in 28 families with the Marfan syndrome and 8 families with four phenotypically related disorders--congenital contractural arachnodactyly (3 families), ectopia lentis (2), mitral-valve prolapse syndrome (2), and annuloaortic ectasia (1). RESULTS: Genetic linkage was established between the Marfan syndrome and only the fibrillin gene on chromosome 15, with a maximum lod score of 25.6 (odds for linkage, 10(25.6):1). Ectopia lentis was also linked to the fibrillin gene on chromosome 15, whereas congenital contractural arachnodactyly was linked to the fibrillin gene on chromosome 5. There was no linkage of mitral-valve prolapse to the fibrillin gene on chromosome 5; studies of chromosome 15 were not informative. Annuloaortic ectasia was not linked to either fibrillin gene. CONCLUSIONS: The Marfan syndrome appears to be caused by mutations in a single fibrillin gene on chromosome 15. Diagnosis of the Marfan syndrome by genetic linkage and analysis is now feasible in many families.

Base Sequence↗