PubMed Health⌕ Search

Biomedical subjects

F M Pope

Publications and source records attributed to F M Pope.

At least 55 records · Page 3Linked to original sources
PubMed1996

An exon skipping mutation of a type V collagen gene (COL5A1) in Ehlers-Danlos syndrome.

The Ehlers-Danlos syndrome (EDS) is a heterogeneous group of inherited connective tissue disorders characterised by skin hyperextensibility, joint hypermobility, easy bruising, and cutaneous fragility. Nine discrete clinical subtypes have been classified. We have investigated the molecular defect in a patient with clinical features of Ehlers-Danlos syndromes types I/II and VII. Electron microscopy of skin tissue indicated abnormal collagen fibrillogenesis with longitudinal sections showing a marked disruption of fibril packing giving very irregular outlines to transverse sections. Analysis of the collagens produced by cultured fibroblasts showed that the type V collagen had a population of alpha 1 (V) chains shorter than normal. Peptide mapping suggested a deletion within the triple helical domain. RTPCR amplification of mRNA covering the whole of this domain of COL5A1 showed a deletion of 54 bp. Although six Gly-X-Y triplets were lost, the essential triplet amino acid sequence and C-propeptide structure were maintained allowing mutant protein chains to be incorporated into triple helices. Genomic DNA analysis identified a de novo G+3-->T transversion in a 5' splice site of one COL5A1 allele. This mutation is analogous to mutations causing exon skipping in the major collagen genes, COL1A1, COL1A2, and COL3A1, identified in several cases of osteogenesis imperfecta and EDS type IV. These observations support the hypothesis that type V, although quantitatively a minor collagen, has a critical role in the formation of the fibrillar collagen matrix.

Adult↗
PubMed1996

COL3A1 mutations cause variable clinical phenotypes including acrogeria and vascular rupture.

We have recently analysed by histological, protein and molecular DNA techniques 23 mutations of the collagen III gene (COL3A1), most of which cause premature arterial fragility, thin skin and variants of vascular Ehlers-Danlos syndrome. There were 14 glycine substitutions between residues 637 and 1021, eight exon skips between exons 7 and 45 and one small inframe deletion. The glycine substitutions produce a gradient of increasingly abnormal clinical phenotypes from exons 36 to 49 while the clinical severity of exon skips is much more variable. Each mutation is private for the affected family or individual concerned having the potential for early prenatal diagnosis and prevention.

Adolescent↗
PubMed1995

Efficient strategy for the detection of mutations in acrogeric Ehlers-Danlos syndrome type IV.

cDNA encoding the C-terminal domain (nt2283 to 3714) of type III collagen was amplified by PCR in five overlapping products and examined for mutations in 13 patients with Ehlers-Danlos syndrome type IV (EDS IV) with uncharacterised lesions and in five control patients with known single base mutations. Six different point mutations were detected by denaturing gradient gel electrophoresis (DGGE), in addition to those in the known controls. Four of seven patients who had no point mutations in this region were shown to lack complete exons from their amplified cDNA. Mutations were detected in all patients with typical or acrogeric EDS IV, but only in one of four individuals with the atypical form of the disease.

Base Sequence↗
PubMed1995

A mother and three daughters with congenital dislocation of the hip and a characteristic facial appearance: a new syndrome?

We describe a mother and her three daughters who all have bilateral congenital dislocation of the hip. The mother has had no other medical problems and is on the 90th centile for height. Her three daughters resemble each other strongly with facial characteristics which include hypertelorism, epicanthic folds, puffiness around the eyes, a flat mid-face and a carp-shaped mouth. All three daughters are on the 3rd centile for height, with their head circumference on a higher centile and all had an ASD. Other features include congenital dislocation of one knee (one), congenital inguinal hernia (one) and vesico-ureteric reflux (one). They also have clinodactyly and hyperextensible finger joints, both features also seen in their father, whose height is on the 3rd centile and who had bilateral congenital inguinal herniae. Collagen studies of skin and ligament were normal. This family does not appear to fit with any of the recognized congenital dislocation syndromes and we suggest that they may represent a previously undescribed syndrome.

Adult↗
PubMed1995

Use of type VII collagen gene (COL7A1) markers in prenatal diagnosis of recessive dystrophic epidermolysis bullosa.

Generalised recessive dystrophic epidermolysis bullosa (EB) is a severe inherited disease in which patients suffer from blistering and scarring of the skin and mucous membranes after minor mechanical trauma. Tight genetic linkage has been established to the type VII collagen gene (COL7A1) at 3p21, with no evidence of locus heterogeneity. Several COL7A1 mutations have now been identified in recessive dystrophic EB patients. Prenatal diagnosis has been performed by examination of a fetal skin biopsy taken at about 16 weeks' gestation, and relies on identification of characteristic ultrastructural and immunohistochemical changes. We have now achieved a first trimester prenatal diagnosis using intragenic and flanking COL7A1 markers in a pregnancy at risk for recessive dystrophic EB. Segregation of the informative markers predicted the baby would be an unaffected carrier. The pregnancy continued to term and a healthy baby was born, confirming this result.

Collagen↗
PubMed1994

Localization of the gene (LAMA4) to chromosome 6q21 and isolation of a partial cDNA encoding a variant laminin A chain.

Laminin is a basement membrane glycoprotein composed of three nonidentical chains, A, B1, and B2. Variant chains such as merosin and S-laminin have been found in different tissues. We have isolated a cDNA encoding a novel laminin A variant that hybridizes to a 6.45-kb mRNA. Using amplification of genomic DNA and flow-sorted chromosomes we have assigned the gene (LAMA4) for this new laminin A variant to chromosome 6. Fluorescence in situ hybridization of a YAC clone further localized the gene to 6q21.

Amino Acid Sequence↗
PubMed1994

Fibrillin secretion and microfibril assembly by Marfan dermal fibroblasts.

The Marfan syndrome has been linked to the FBN1 gene encoding the microfibrillar glycoprotein fibrillin. To date, there have been no descriptions of microfibrillar abnormalities characteristic of this connective tissue disorder, although biochemical analyses have highlighted apparent abnormalities in fibrillin synthesis, secretion and processing. We have conducted a biochemical and ultrastructural investigation of fibrillin expression and assembly by a panel of dermal fibroblast lines from patients with Marfan syndrome and related diseases. The study has highlighted marked differences between cells in terms of secretion and aggregation of newly-synthesised fibrillin. In addition, electron microscopic visualization of fibrillin assemblies has clearly demonstrated for the first time the plethora of microfibrillar abnormalities that underlie this heterogeneous disorder. These data emphasize the molecular complexity that is a feature of the diverse clinical phenotypes exhibited by Marfan patients.

Autoradiography↗
PubMed1994

Stickler syndrome: correlation between vitreoretinal phenotypes and linkage to COL 2A1.

Stickler syndrome is an autosomal dominantly inherited condition characterised by ocular, articular, facial, auditory and oral features. There is locus heterogeneity with about two thirds of families showing linkage to the gene encoding type II procollagen (COL 2A1). Clinical overlap with Marshall's, Wagner's and other syndromes has caused considerable confusion but the importance of the congenital vitreous anomaly, as first described by Scott, has not previously been emphasised. This study examines the linkage of two vitreo-retinal phenotype subgroups of Stickler syndrome to COL 2A1. A total of 97 affected patients from 24 pedigrees were examined. This is the largest published series of Stickler syndrome patients to date and all have undergone full clinical and ophthalmological examination by a single investigator. A clinical classification is proposed based on vitreoretinal phenotype. All patients demonstrating the congenital vitreous anomaly have been designated Stickler syndrome type 1 and those without the congenital vitreous anomaly as Stickler syndrome type 2 patients. There were 69 affected patients from 20 unrelated type 1 pedigrees and 28 affected patients from 4 unrelated type 2 pedigrees. Using two markers at the COL 2A1 locus, Stickler syndrome type 1 pedigrees showed complete linkage to COL 2A1 with a maximum lod score of 12.33 at zero recombination. Linkage to COL 2A1 was excluded in the two type 2 pedigrees that were informative. From these data it appears that this clinical classification is a useful first step in resolving the genetic heterogeneity in this condition.

Base Sequence↗
PubMed1994

A family with Ehlers-Danlos syndrome type III/articular hypermobility syndrome has a glycine 637 to serine substitution in type III collagen.

Ehlers-Danlos syndrome (EDS) is a heterogeneous group of heritable disorders of connective tissue. The type III variety is characterized by joint hypermobility and minor hyperextensibility and softness of the skin. While collagen fibril structure has been shown to be abnormal in such patients, the underlying molecular defect(s) has not been determined. Here we characterize the first mutation found in a family with EDS III. Analysis of cultured fibroblasts from the affected family revealed intracellular retention of type III collagen. This is usually a biochemical characteristic of EDS IV, caused by mutations of COL3A1. Analysis of the cDNA sequence in this EDS III family revealed a glycine to serine mutation at amino acid residue 637 of the type III collagen molecule. This was confirmed by allele-specific oligonucleotide hybridization against amplified genomic DNA. Thus mutations of type III collagen can cause either EDS IV or EDS III. Two affected family members had virtually normal skin and so more closely resembled the phenotype of articular hypermobility syndrome.

Adult↗
PubMed1994

Genetic linkage to the type VII collagen gene (COL7A1) in 26 families with generalised recessive dystrophic epidermolysis bullosa and anchoring fibril abnormalities.

To strengthen the evidence for genetic linkage to COL7A1, we have studied 26 generalised recessive dystrophic epidermolysis bullosa (EB) families of British, Italian, Irish, and South African origin. We chose two linkage markers, a COL7A1 PvuII intragenic polymorphism and a highly informative anonymous microsatellite marker, D3S1100, which maps close to the COL7A1 locus at 3p21.1-3. Diagnosis was established by family history, clinical examination, immunofluorescence, and ultrastructural studies. The PvuII marker was informative in 16 families with a maximum lod score (Zmax) of 3.51 at recombination fraction (theta) = 0. The D3S1100 microsatellite was informative in 24 out of 25 families with Zmax = 6.8 at theta = 0.05 (Z = 4.94 at theta = 0) and no obligatory recombination events. These data strongly suggest that COL7A1 mutations cause EB in these families and, combined with previous studies, indicate locus homogeneity. The importance of anchoring fibrils for dermal-epidermal adhesion is further underlined. D3S1100 may later prove useful in prenatal diagnosis of this disease, if used in combination with other markers.

Base Sequence↗
PubMed1993

The gene responsible for Werner syndrome may be a cell division "counting" gene.

Werner syndrome is a rare, autosomal, recessive condition that is frequently studied as a model of some aspects of human aging, although the behavioral changes that are usually associated with old age are only seen very infrequently. A most striking aspect of the phenotype of Werner syndrome, presumably arising from the same gene defect, is a dramatic shortening of the replicative life-span of dermal fibroblasts in vitro. The finite replicative life-span of human cells in vitro is due to the stochastic loss of replicative ability in a continuously increasing fraction of newborn cells at every generation. Normal human fibroblasts achieve approximately 60 population doublings in culture, while Werner syndrome cells usually only achieve approximately 20 population doublings. We describe an analysis of the replicative ability of fibroblasts from Werner syndrome patients and demonstrate that the cells in these cultures usually exit, apparently irreversibly, from the cell cycle at a faster rate than do normal cells, although they mostly start off with a good replicative ability. We propose that the Werner syndrome gene is a "counting" gene controlling the number of times that human cells are able to divide before terminal differentiation.

Adult↗
PubMed1993

Single base mutation that substitutes glutamic acid for glycine 1021 in the COL3A1 gene and causes Ehlers-Danlos syndrome type IV.

The proposita described here was a 24-year-old woman with an acrogeric form of the Ehlers-Danlos syndrome including a massive dissecting aortic aneurysm. She was found to have a single-base mutation that substituted glutamic acid for glycine at amino acid position 1021 in the triple-helical domain of the type III procollagen. It is the most carboxy-terminal single-base mutation characterized to date in the COL3A1 gene. Analysis of medium and cell layer proteins from proposita's cultured skin fibroblasts showed that the mutant protein was poorly secreted, migrated more slowly on a polyacrylamide gel, and was partially unstable at +25 degrees C to brief digestion with trypsin.

Adult↗
PubMed1993

Giant aneurysm of internal carotid artery in a four-year-old child: a case report.

A case of giant saccular aneurysm in early childhood is reported. An internal carotid aneurysm presenting with episodic headache was successfully clipped with complete relief of symptoms. The patient was also investigated for a possible collagen deficiency which proved negative. Clinical features and pathogenesis of this rare lesion are discussed.

Carotid Artery Diseases↗