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P H Byers

Publications and source records attributed to P H Byers.

At least 19 recordsLinked to original sources
PubMed2003

Neurological presentation of Ehlers-Danlos syndrome type IV in a family with parental mosaicism.

Ehlers-Danlos syndrome type IV (EDS-IV) is an autosomal-dominant disorder caused by a defect of type III collagen which leads to ruptures of arteries and hollow organs. Neurological presentation with muscle involvement and flexion contractures of the finger joints is uncommon. We clinically characterized seven members of a family with EDS-IV. The index patient, a young woman with an acrogeric face, suffered chronic muscle pain and cramps, Achilles tendon retraction, finger flexion contractures and seizures. The mother had similar features and had experienced an ischemic stroke. Biochemical study in cultured fibroblasts and molecular analysis of the COL3A1 gene led to the diagnosis of EDS-IV. A glycine substitution, p.G883V, within the triple helix of the alpha 1(III) chain, was found in the index patient and in the mother. The maternal grandfather and an aunt each had an abdominal aortic aneurysm, the rupture of which was the cause of death in the latter, at 40 years of age. Surprisingly, we found the mutation, as a mosaic, in the asymptomatic maternal grandmother. This expands the clinical spectrum of EDS type IV and confirms that in some families mosaicism can be identified as the source of the mutation.

Adult↗
PubMed2002

A single amino acid substitution (D1441Y) in the carboxyl-terminal propeptide of the proalpha1(I) chain of type I collagen results in a lethal variant of osteogenesis imperfecta with features of dense bone diseases.

Osteogenesis imperfecta (OI) is characterised by brittle bones and caused by mutations in the type I collagen genes, COL1A1 and COL1A2. We identified a mutation in the carboxyl-terminal propeptide coding region of one COL1A1 allele in an infant who died with an OI phenotype that differed from the usual lethal form and had regions of increased bone density. The newborn female had dysmorphic facial features, including loss of mandibular angle. Bilateral upper and lower limb contractures were present with multiple fractures in the long bones and ribs. The long bones were not compressed and their ends were radiographically dense. She died after a few hours and histopathological studies identified extramedullary haematopoiesis in the liver, little lamellar bone formation, decreased osteoclasts, abnormally thickened bony trabeculae with retained cartilage in long bones, and diminished marrow spaces similar to those seen in dense bone diseases such as osteopetrosis and pycnodysostosis. The child was heterozygous for a COL1A1 4321G-->T transversion in exon 52 that changed a conserved aspartic acid to tyrosine (D1441Y). Abnormal proalpha1(I) chains were slow to assemble into dimers and trimers, and abnormal molecules were retained intracellularly for an extended period. The secreted type I procollagen molecules synthesised by cultured dermal fibroblasts were overmodified along the full length but had normal thermal stability. These findings suggest that the unusual phenotype reflected both a diminished amount of secreted type I procollagen and the presence of a population of stable and overmodified molecules that might support increased mineralisation or interfere with degradation of bone.

Amino Acid Substitution↗
PubMed2002

Testing for osteogenesis imperfecta in cases of suspected non-accidental injury.

To evaluate if laboratory testing for osteogenesis imperfecta (OI) identifies children unrecognised by clinical examination in instances where non-accidental injury (NAI) is suspected as the likely cause of fracture, we carried out a retrospective review of available medical records and biochemical test results from 262 patients. Cultured fibroblasts were received for biochemical testing for OI from children in whom the diagnosis of NAI was suspected. Eleven of the samples had alterations in the amount or structure of type I collagen synthesised, consistent with the diagnosis of OI, and in 11 others we could not exclude OI. Referring physicians correctly identified children with OI in six of the 11 instances established by biochemical studies, did not identify OI by clinical examination in three, and there was inadequate clinical information to know in two others. Biochemical testing was inconclusive in 11 infants in whom the diagnosis of OI could not be excluded, none of whom were thought to be affected by the referring clinicians. Four children believed to have OI by clinical examination had normal biochemical studies, a false positive clinical diagnosis attributed, in large part, to the use of scleral hue (a feature that is age dependent) as a major diagnostic criterion. Given the inability to identify all children with OI by clinical examination in situations of suspected NAI, laboratory testing for OI (and other genetic predispositions for fractures) is a valuable adjunct in discerning the basis for fractures and may identify a small group of children with previously undiagnosed OI.

Adult↗
PubMed2001

Haploinsufficiency for one COL3A1 allele of type III procollagen results in a phenotype similar to the vascular form of Ehlers-Danlos syndrome, Ehlers-Danlos syndrome type IV.

Mutations in the COL3A1 gene that encodes the chains of type III procollagen result in the vascular form of Ehlers-Danlos syndrome (EDS), EDS type IV, if they alter the sequence in the triple-helical domain. Although other fibrillar collagen-gene mutations that lead to allele instability or failure to incorporate proalpha-chains into trimers-and that thus reduce the amount of mature molecules produced-result in clinically apparent phenotypes, no such mutations have been identified in COL3A1. Furthermore, mice heterozygous for Col3a1 "null" alleles have no identified phenotype. We have now found three frameshift mutations (1832delAA, 413delC, and 555delT) that lead to premature termination codons (PTCs) in exons 27, 6, and 9, respectively, and to allele-product instability. The mRNA from each mutant allele was transcribed efficiently but rapidly degraded, presumably by the mechanisms of nonsense-mediated decay. In a fourth patient, we identified a point mutation, in the final exon, that resulted in a PTC (4294C-->T [Arg1432Ter]). In this last instance, the mRNA was stable but led to synthesis of a truncated protein that was not incorporated into mature type III procollagen molecules. In all probands, the presenting feature was vascular aneurysm or rupture. Thus, in contrast to mutations in genes that encode the dominant protein of a tissue (e.g., COL1A1 and COL2A1), in which "null" mutations result in phenotypes milder than those caused by mutations that alter protein sequence, the phenotypes produced by these mutations in COL3A1 overlap with those of the vascular form of EDS. This suggests that the major effect of many of these dominant mutations in the "minor" collagen genes may be expressed through protein deficiency rather than through incorporation of structurally altered molecules into fibrils.

Alleles↗
PubMed2001

Folding defects in fibrillar collagens.

Fibrillar collagens have a long triple helix in which glycine is in every third position for more than 1000 amino acids. The three chains of these molecules are assembled with specificity into several different molecules that have tissue-specific distribution. Mutations that alter folding of either the carboxy-terminal globular peptides that direct chain association, or of the regions of the triple helix that are important for nucleation, or of the bulk of the triple helix, all result in identifiable genetic disorders in which the phenotype reflects the region of expression of the genes and their tissue-specific distribution. Mutations that result in changed amino-acid sequences in any of these regions have different effects on folding and may have different phenotypic outcomes. Substitution for glycine residues in the triple helical domains are among the most common effects of mutations, and the nature of the substituting residue and its location in the chain contribute to the effect on folding and also on the phenotype. More complex mutations, such as deletions or insertions of triple helix, also affect folding, probably because of alterations in helical pitch along the triple helix. These mutations all interfere with the ability of these molecules to form the characteristic fibrillar array in the extracellular matrix and many result in intracellular retention of abnormal molecules.

Amino Acid Substitution↗
PubMed2001

Deletions and duplications of Gly-Xaa-Yaa triplet repeats in the triple helical domains of type I collagen chains disrupt helix formation and result in several types of osteogenesis imperfecta.

Triple helix formation is a prerequisite for the passage of type I procollagen from the endoplasmic reticulum and secretion from the cell to form extracellular fibrils that will support mineral deposition in bone. Analysis of cDNA from 11 unrelated individuals with osteogenesis imperfecta (OI) revealed the presence of 11 novel, short in-frame deletions or duplications of three, nine, or 18 nucleotides in the helical coding regions of the COL1A1 and COL1A2 collagen genes. Triple helix formation was impaired, type I collagen alpha chains were post-translationally overmodified, and extracellular secretion was markedly reduced. With one exception, the obligate Gly-Xaa-Yaa repeat pattern of amino acids in the helical domains was not altered, but the Xaa- and Yaa position residues were out of register relative to the amino acid sequences of adjacent chains in the triple helix. Thus, the identity of these amino acids, in addition to third position glycines, is important for normal helix formation. These findings expand the known repertoire of uncommon in-frame deletions and duplications in OI, and provide insight into normal collagen biosynthesis and collagen triple helix formation.

Amino Acid Motifs↗
PubMed2001

Osteogenesis imperfecta: mode of delivery and neonatal outcome.

OBJECTIVE: To evaluate the pregnancy characteristics, methods of delivery, and neonatal outcomes of fetuses affected by osteogenesis imperfecta. METHODS: We reviewed medical records of 1016 individuals whose cells were sent to the University of Washington Collagen Diagnostic Laboratory between 1987 and 1994 for confirmation of diagnoses of osteogenesis imperfecta. Information and neonatal records were available for 167 of those pregnancies. From those we identified method(s) of prenatal detection, delivery method, and neonatal complications, including survival and acquisition of new fractures, and related them to type of delivery. RESULTS: The cesarean delivery rate was 54%, most of them (53%) for nonvertex presentation and fewer than 15% because of an antenatal diagnoses of osteogenesis imperfecta. There was an unusually high rate of breech presentation at term (37%). In infants with nonlethal forms of osteogenesis imperfecta, 24 of 59 (40%) delivered by cesarean and 17 of 53 (32%) delivered vaginally had new fractures (chi(2) =.89; P =.3). Among 55 infants with the most severe form, 24 of 31 delivered by cesarean and 21 of 24 delivered vaginally died within 2 weeks of birth. CONCLUSION: Cesarean delivery did not decrease fracture rates at birth in infants with nonlethal forms of osteogenesis imperfecta nor did it prolong survival for those with lethal forms. Prenatal diagnosis did not influence mode of delivery in most instances. Most cesarean deliveries were done for usual obstetric indications.

Breech Presentation↗
PubMed2001

Disruption of one intra-chain disulphide bond in the carboxyl-terminal propeptide of the proalpha1(I) chain of type I procollagen permits slow assembly and secretion of overmodified, but stable procollagen trimers and results in mild osteogenesis imperfecta.

Type I procollagen is a heterotrimer comprised of two proalpha1(I) chains and one proalpha2(I) chain. Chain recognition, association, and alignment of proalpha chains into correct registration are thought to occur through interactions between the C-terminal propeptide domains of the three chains. The C-propeptide of each chain contains a series of cysteine residues (eight in proalpha1(I) and seven in proalpha2(I)), the last four of which form intra-chain disulphide bonds. The remaining cysteine residues participate in inter-chain stabilisation. Because these residues are conserved, they are thought to be important for folding and assembly of procollagen. We identified a mutation (3897C-->G) that substituted tryptophan for the cysteine at position 1299 in proalpha1(I) (C1299W, the first cysteine that participates in intra-chain bonds) and resulted in mild osteogenesis imperfecta. The patient was born with a fractured clavicle and four rib fractures. By 18 months of age he had had no other fractures and was on the 50th centile for length and weight. The proband's mother, maternal aunt, and grandfather had the same mutation and had few fractures, white sclerae, and discoloured teeth, but their heights were within the normal range. In the patient's cells the defective chains remained as monomers for over 80 minutes (about four times normal) and were overmodified. Some secreted procollagens were also overmodified but had normal thermal stability, consistent with delayed, but normal helix formation. This intra-chain bond may stabilise the C-propeptide and promote rapid chain association. Other regions of the C-propeptide thus play more prominent roles in chain registration and triple helix nucleation.

Amino Acid Sequence↗
PubMed2000

Null alleles of the COL5A1 gene of type V collagen are a cause of the classical forms of Ehlers-Danlos syndrome (types I and II).

Ehlers-Danlos syndrome (EDS) types I and II, which comprise the classical variety, are well characterized from the clinical perspective, but it has been difficult to identify the molecular basis of the disorder in the majority of affected individuals. Several explanations for this failure to detect mutations have been proposed, including genetic heterogeneity, failure of allele expression, and technical difficulties. Genetic heterogeneity has been confirmed as an explanation for such failure, since causative mutations have been identified in the COL5A1, COL5A2, and tenascin X genes and since they have been inferred in the COL1A2 gene. Nonetheless, in the majority of families with autosomal dominant inheritance of EDS, there appears to be linkage to loci that contain the COL5A1 or COL5A2 genes. To determine whether allele-product instability could explain failure to identify some mutations, we analyzed polymorphic variants in the COL5A1 gene in 16 individuals, and we examined mRNA for the expression of both alleles and for alterations in splicing. We found a splice-site mutation in a single individual, and we determined that, in six individuals, the mRNA from one COL5A1 allele either was not expressed or was very unstable. We identified small insertions or deletions in five of these cell strains, but we could not identify the mutation in the sixth individual. Thus, although as many as one-half of the mutations that give rise to EDS types I and II are likely to lie in the COL5A1 gene, a significant portion of them result in very low levels of mRNA from the mutant allele, as a consequence of nonsense-mediated mRNA decay.

Adolescent↗
PubMed2000

Clinical and genetic features of Ehlers-Danlos syndrome type IV, the vascular type.

BACKGROUND: Ehlers-Danlos syndrome type IV, the vascular type, results from mutations in the gene for type III procollagen (COL3A1). Affected patients are at risk for arterial, bowel, and uterine rupture, but the timing of these events, their frequency, and the course of the disease are not well documented. METHODS: We reviewed the clinical and family histories of and medical and surgical complications in 220 index patients with biochemically confirmed Ehlers-Danlos syndrome type IV and 199 of their affected relatives. We identified the underlying COL3A1 mutation in 135 index patients. RESULTS: Complications were rare in childhood; 25 percent of the index patients had a first complication by the age of 20 years, and more than 80 percent had had at least one complication by the age of 40. The calculated median survival of the entire cohort was 48 years. Most deaths resulted from arterial rupture. Bowel rupture, which often involved the sigmoid colon, accounted for about a quarter of complications but rarely led to death. Complications of pregnancy led to death in 12 of the 81 women who became pregnant. The types of complications were not associated with specific mutations in COL3A1. CONCLUSIONS: Although most affected patients survive the first and second major complications, Ehlers-Danlos syndrome type IV results in premature death. The diagnosis should be considered in young people who come to medical attention because of uterine rupture during pregnancy or arterial or visceral rupture.

Adolescent↗
PubMed2000

Partial COL1A2 gene duplication produces features of osteogenesis imperfecta and Ehlers-Danlos syndrome type VII.

Type I collagen is the most abundant structural protein in the mammalian body. It exists as a heterotrimer of two subunits in the form [alpha1(I)]2alpha2(I). Pathogenic mutations in COL1A1 and COL1A2, the genes that encode the two subunits, cause a range of phenotypes including mild to lethal forms of osteogenesis imperfecta and a restricted set of Ehlers-Danlos syndrome phenotypes. Lethal mutations usually result from missense mutations that disrupt the normal triple helical structure of the molecule. Multi-exon duplication or deletion in type I collagen genes has rarely been observed and has generally resulted in a lethal or severe phenotype. We report a partial duplication in the COLIA2 gene that causes a relatively mild phenotype, despite the addition of 477 amino acids to the triple helical domain of the proalpha2(I) chain. The abnormal molecule is synthesized and secreted by cultured dermal fibroblasts in a normal fashion. Electron microscopy of dermal tissue reveals small but otherwise near normal collagen fibrils. The gene duplication occurred by mitotic sister chromatid exchange in the mother who is mosaic for the duplication allele. Examination of the abnormal sequence suggests a means by which the duplicated molecule could be processed and properly incorporated into mature collagen fibrils.

Base Sequence↗
PubMed2000

Collagens: building blocks at the end of the development line.

Collagens are some of the major building blocks of the vertebrate body. In addition to their structural role, they are important for cell guidance during development and for maintaining tissue integrity. In their absence, phenotypes range from lethal to mild. These studies demonstrate that collagens,in their rich array, play important roles in development and are significant elements in reading the developmental code.

Animals↗
PubMed2000

Osteogenesis imperfecta: perspectives and opportunities.

The last 2 years have seen additions proposed to the very limited armamentarium of treatments for osteogenesis imperfecta. These include the use of bisphosphonates to decrease bone resorption, growth hormone to augment growth and collagen production, and bone marrow transplantation to create chimeras at the level of the collagen production unit in bone. Although there are optimistic proponents for each strategy, the lack of well-controlled studies and the absence of clearly defined objectives for therapy hinder clear assessment.

Humans↗
PubMed1999

Large kindred with Ehlers-Danlos syndrome type IV due to a point mutation (G571S) in the COL3A1 gene of type III procollagen: low risk of pregnancy complications and unexpected longevity in some affected relatives.

Ehlers-Danlos syndrome (EDS) type IV is an autosomal dominant connective tissue disorder. Early morbidity and mortality results from rupture of vessels and internal organs. A large kindred with EDS type IV was studied clinically, and the biochemical defects and underlying mutation in the COL3A1 gene that encodes the chains of type III procollagen were identified. A G-->A transition results in a single amino acid substitution, G571S, in the triple helical domain of the products of one COL3A1 allele. Although the clinical findings seen on examination are characteristic of EDS type IV, longevity is longer than that seen in many families and there is less pregnancy-associated morbidity or mortality than in some families. This suggests that some clinical aspects of EDS type IV may be related to the nature of the mutation and its effect on the behavior of the protein.

Ehlers-Danlos Syndrome↗