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Biomedical subjects

F M Pope

Publications and source records attributed to F M Pope.

At least 19 recordsLinked to original sources
PubMed2003

A glycine to aspartic acid substitution of COL2A1 in a family with the Strudwick variant of spondyloepimetaphyseal dysplasia.

BACKGROUND: Spondyloepimetaphyseal dysplasia (SEMD) is one of a clinically heterogeneous group of skeletal disorders, characterized by defective growth and modelling of the spine and long bones. Common clinical features include disproportionate short stature, malformed vertebrae and abnormal epiphyses or metaphyses. Some cases have been associated with mutations in the COL2A1 gene. AIM: To determine whether the autosomal dominant Strudwick-type SEMD in a three-generation family, showing specific phenotypical features such as chest deformity, limb shortening, myopia and early-onset degenerative osteoarthrosis, might be caused by a novel COL2A1 mutation. DESIGN: Genetic testing and clinical examination of family members. METHODS: Direct sequencing of PCR-amplified genomic DNA from the COL2A1 gene. RESULTS: A point mutation within exon 20 of the COL2A1 gene was identified that substituted a glycine for an aspartic acid residue at codon 262. DISCUSSION: All previously reported autosomal dominant mutations causing SEMD have substituted an obligate glycine within the triple helix, in particular at codons 292, 304 and 709 in the three reported Strudwick-type patients. Additionally, a recurrent glycine substitution at codon 154 has been identified in two unrelated Finnish cases with radiological features consistent with the Strudwick subtype. Our sixth helical glycine substitution extends the mutational spectrum and genotype/phenotype correlations of Strudwick-type SEMD.

Aspartic Acid↗
PubMed2002

Severe panniculitis caused by homozygous ZZ alpha1-antitrypsin deficiency treated successfully with human purified enzyme (Prolastin).

Severe panniculitis caused by alpha1-antitrypsin deficiency is very rare even though the ZZ phenotype occurs in 1 : 3500 of the population of northern Europe. We describe a 33-year-old woman with rapidly progressing panniculitis and extensive skin necrosis with multiple life-threatening complications. Initial treatment followed by maintenance therapy with human purified enzyme (Prolastin, Bayer, Bridgend, U.K.) has been life-saving.

Adult↗
PubMed2002

Vitreoretinopathy with phalangeal epiphyseal dysplasia, a type II collagenopathy resulting from a novel mutation in the C-propeptide region of the molecule.

A large family with dominantly inherited rhegmatogenous retinal detachment, premature arthropathy, and development of phalangeal epiphyseal dysplasia, resulting in brachydactyly was linked to COL2A1, the gene encoding proalpha1(II) collagen. Mutational analysis of the gene by exon sequencing identified a novel mutation in the C-propeptide region of the molecule. The glycine to aspartic acid change occurred in a region that is highly conserved in all fibrillar collagen molecules. The resulting phenotype does not fit easily into pre-existing subgroups of the type II collagenopathies, which includes spondyloepiphyseal dysplasia, and the Kniest, Strudwick, and Stickler dysplasias.

Adult↗
PubMed2001

A spectrum of ABCC6 mutations is responsible for pseudoxanthoma elasticum.

To better understand the pathogenetics of pseudoxanthoma elasticum (PXE), we performed a mutational analysis of ATP-binding cassette subfamily C member 6 (ABCC6) in 122 unrelated patients with PXE, the largest cohort of patients yet studied. Thirty-six mutations were characterized, and, among these, 28 were novel variants (for a total of 43 PXE mutations known to date). Twenty-one alleles were missense variants, six were small insertions or deletions, five were nonsense, two were alleles likely to result in aberrant mRNA splicing, and two were large deletions involving ABCC6. Although most mutations appeared to be unique variants, two disease-causing alleles occurred frequently in apparently unrelated individuals. R1141X was found in our patient cohort at a frequency of 18.8% and was preponderant in European patients. ABCC6del23-29 occurred at a frequency of 12.9% and was prevalent in patients from the United States. These results suggested that R1141X and ABCC6del23-29 might have been derived regionally from founder alleles. Putative disease-causing mutations were identified in approximately 64% of the 244 chromosomes studied, and 85.2% of the 122 patients were found to have at least one disease-causing allele. Our results suggest that a fraction of the undetected mutant alleles could be either genomic rearrangements or mutations occurring in noncoding regions of the ABCC6 gene. The distribution pattern of ABCC6 mutations revealed a cluster of disease-causing variants within exons encoding a large C-terminal cytoplasmic loop and in the C-terminal nucleotide-binding domain (NBD2). We discuss the potential structural and functional significance of this mutation pattern within the context of the complex relationship between the PXE phenotype and the function of ABCC6.

ATP-Binding Cassette Transporters↗
PubMed2001

The Buschke-Ollendorff syndrome presenting as familial elastic tissue naevi.

We present a family with Buschke-Ollendorff syndrome presenting as elastic tissue naevi without evidence of osteopoikilosis. We discuss the variable expression of this syndrome in other families previously reported in the literature, the association of various connective tissue abnormalities and their correlation with the pathogenesis of this interesting condition.

Connective Tissue Diseases↗
PubMed2001

Elastosis perforans serpiginosa and associated disorders.

We report elastosis perforans serpiginosa (EPS) arising in three patients with Ehlers-Danlos syndrome, osteogenesis imperfecta and Down's syndrome. These cases illustrate some of the rare but well-recognized disease associations with EPS. The other causes of EPS are reviewed.

Adolescent↗
PubMed2000

A light and electron microscopic study of osteogenesis imperfecta bone samples, with reference to collagen chemistry and clinical phenotype.

A detailed morphological study was carried out using light and electron microscopy on 36 bone specimens from patients suffering from osteogenesis imperfecta (OI) and 20 age- and site-matched control bone specimens. The findings were grouped into the clinical types of OI according to the Sillence classification. The morphological and ultrastructural alterations observed in OI bone correlate well with clinical severity. Thus, OI type I, the mildest type, showed the least abnormalities in bone ultrastructure. OI type IV closely resembled type I, with only minor abnormalities in the bone cells and osteoid. OI type III showed abnormalities in the structure and distribution of osteoid collagen fibrils, whilst OI type II, the lethal form, revealed many varied abnormalities such as thin cortical bone, sparse trabecular bone, increased numbers of osteoclasts and osteocytes, thin osteoid with thin collagen fibrils, and patchy mineralization.

Adolescent↗
PubMed2000

Emergency repair of type A aortic dissection in type IV Ehlers-Danlos syndrome.

Ehlers-Danlos syndrome type IV is a distinctive syndrome in which thin and fragile skin, premature ageing, bruising and scarring are combined with lethal or life-threatening arterial weakness. Aortic rupture either at the aortic root and arch, or sometimes lower down the artery, are particularly characteristic. Even quite minor injury can produce dangerous vascular tearing and damage. Technical difficulties encountered in arterial repair or venous ligature are particularly worrying. The authors report the treatment of a ruptured type A aortic dissection associated with Ehlers-Danlos syndrome where the extreme fragility of the tissues and tendency to bleed posed a difficult task for the surgeon.

Adult↗
PubMed2000

Mutations in a gene encoding an ABC transporter cause pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a heritable disorder characterized by calcification of elastic fibres in skin, arteries and retina that results in dermal lesions with associated laxity and loss of elasticity, arterial insufficiency and retinal haemorrhages leading to macular degeneration. PXE is usually found as a sporadic disorder, but examples of both autosomal recessive and autosomal dominant forms of PXE have been observed. Partial manifestations of the PXE phenotype have also been described in presumed carriers in PXE families. Linkage of both dominant and recessive forms of PXE to a 5-cM domain on chromosome 16p13.1 has been reported (refs 8,9). We have refined this locus to an 820-kb region containing 6 candidate genes. Here we report the exclusion of five of these genes and the identification of the first mutations responsible for the development of PXE in a gene encoding a protein associated with multidrug resistance (ABCC6).

ATP-Binding Cassette Transporters↗
PubMed2000

COL2A1 exon 2 mutations: relevance to the Stickler and Wagner syndromes.

AIMS: To compare the clinical and molecular genetic features of two phenotypically distinct subgroups of families with type 1 Stickler syndrome. BACKGROUND: Stickler syndrome (hereditary arthro-ophthalmopathy, McKusick Nos 108300 and 184840) is a dominantly inherited disorder of collagen connective tissue, resulting in an abnormal vitreous, myopia, and a variable degree of orofacial abnormality, deafness, and arthropathy. Stickler syndrome is the commonest inherited cause of rhegmatogenous retinal detachment in childhood with a risk of giant retinal tear (GRT) which is commonly bilateral and a frequent cause of blindness. METHOD: Pedigrees were identified from the vitreoretinal service database and subclassified according to vitreoretinal phenotype. Ophthalmic, skeletal, auditory, and orofacial features were assessed. Linkage analysis was carried out with markers for the candidate genes COL2A1, COL11A1, and COL11A2. The COL2A1 gene was amplified as five overlapping PCR products. Direct sequencing of individual exons identified mutations. RESULTS: Eight families exhibiting the type 1 vitreous phenotype were studied. Seven were consistent for linkage to COL2A1, with lod scores ranging from 2.1 to 0.3. In most instances linkage to COL11A1 and COL11A2 could be excluded. One family was analysed without prior linkage analysis. Three of the families exhibited a predominantly ocular phenotype with minimal or absent systemic involvement and were found to have mutations in exon 2 of COL2A1. Five other pedigrees with an identical ocular phenotype plus orofacial, auditory, and articular involvement had mutations in others regions of the COL2A1 gene. None of the pedigrees exhibited the characteristic lenticular, retinal pigment epithelial, or choroidal changes seen in Wagner syndrome. CONCLUSIONS: These data confirm that type 1 Stickler syndrome is caused by mutations in the gene encoding type II collagen (COL2A1). In addition, data are submitted showing that mutations involving exon 2 of COL2A1 are characterised by a predominantly ocular variant of this disorder, consistent with the major form of type II procollagen in non-ocular tissues having exon 2 spliced out. Such patients are all at high risk of retinal detachment. This has important implications for counselling patients with regard to the development of systemic complications. It also emphasises the importance and reliability of the ophthalmic examination in the differential diagnosis of this predominantly ocular form of Stickler syndrome from Wagner's vitreoretinopathy.

Collagen↗
PubMed1999

Pseudoxanthoma elasticum maps to an 820-kb region of the p13.1 region of chromosome 16.

We have performed linkage analysis on 21 families with pseudoxanthoma elasticum (PXE) using 10 polymorphic markers located on chromosome 16p13.1. The gene responsible for the PXE phenotype was localized to an 8-cM region of 16p13.1 between markers D16S500 and D16S3041 with a maximum lod score of 8.1 at a recombination fraction of 0.04 for marker D16S3017. The lack of any locus heterogeneity suggests that the major predisposing allele for the PXE phenotype is located in this region. Haplotype studies of a total of 36 PXE families identified several recombinations that further confined the PXE gene to a region (< 1 cM) between markers D16S3060 and D16S79. This PXE locus was identified within a single YAC clone and several overlapping BAC recombinants. From sequence analysis of these BAC recombinants, it is clear that the distance between markers D16S3060 and D16S79 is about 820 kb and contains a total of nine genes including three pseudogenes. We predict that mutations in one of the expressed genes in the locus will be responsible for the PXE phenotype in these families.

Alleles↗
PubMed1999

Morphometric analysis of type I collagen fibrils in the osteoid of osteogenesis imperfecta.

Electron microscopy and morphometric measurements of bone osteoid collagen diameter from 42 osteogenesis imperfecta (OI) patients and 25 age- and site-matched controls were carried out. Although the mean diameter did not correlate well with the severity of the disease, it related well with the clinical types and revealed collagen fibrils of reduced diameter in the osteoid of all OI types. Thus, OI type II (the severest type) demonstrated the smallest diameter (45 nm), followed by OI type I (the mildest form) with a mean diameter of 57 nm. The diameter obtained for type III (67 nm) and type IV (64 nm) was lower than the normal control mean diameter (73 nm) but did not show a statistical difference. The thinner fibrils observed in OI bone may be unable to provide nucleating and scaffolding sites for mineral propagation and may play a role in the fragility of bone in this disease.

Adolescent↗