Biomedical subjects

H W Lehmann

Publications and source records attributed to H W Lehmann.

6 recordsLinked to original sources

PubMed1998

Identification of a new heterozygous point mutation in the COL1A2 gene leading to skipping of exon 9 in a patient with joint laxity, hyperextensibility of skin and blue sclerae. Mutations in brief no. 166. Online.

A heterozygous deletion of exon 9 in the COL1A2-mRNA of a patient with symptoms of both the Ehlers-Danlos-Syndrome and the Osteogensis Imperfecta is described. In the genomic DNA of the patient, exon 9 is homozygously present. We identified a novel heterozygous point mutation in the splice donor site of intron 9, leading to a G-->A substitution in position +5. This mutation leads to heterozygous skipping of exon 9 in the COL1A2-mRNA of this patient. The deletion results in a shortened (by 18 amino acids) but in frame 12(1) chain, which probably leads to the formation of abberantly processed triple helices.

Alternative Splicing↗

PubMed1995

Composition and posttranslational modification of individual collagen chains from osteosarcomas and osteofibrous dysplasias.

The composition of collagen was analyzed and the degree of lysyl hydroxylation of individual collagen chains was determined in four osteosarcomas and two osteofibrous dysplasias. In addition, the tumor proliferation (number of mitoses, proliferating-nuclear-antigen-positive cells, MIB) as well as the response to chemotherapy (morphological regression grade) were checked. All tumors contained a high proportion of collagen III and, in all but one osteosarcoma, pepsin-extracted collagens I and III were overmodified. Furthermore, the proportion of diglycosides in collagen I was about four times higher than in controls. The collagen composition and modification resembled those of bones at early stages of human development. One osteosarcoma and both osteofibrous dysplasias were in the normal range of lysyl hydroxylation. There was no correlation between the collagen properties and the histopathological marker of tumor proliferation.

Adolescent↗

PubMed1995

Hydroxylation of collagen type I: evidence that both lysyl and prolyl residues are overhydroxylated in osteogenesis imperfecta.

The composition of the collagens secreted into the media of fibroblast cultures of 39 patients with osteogenesis imperfecta (OI) was the same in controls and OI cultures. An abnormal migration pattern of collagens upon SDS-PAGE was evident in one third of the cultures investigated. Lysyl and prolyl hydroxylation of HPLC-purified alpha 1(I) chains was elevated in about 60% of cultures. The degree of hydroxylation was highest in the lethal forms. The extent of lysyl and prolyl hydroxylation showed a strong correlation (r = 0.74, P < 0.001). While high levels of hydroxylation are frequently observed in OI patients, a direct correlation between lysyl or prolyl hydroxylation and fracture rate or growth retardation could not be established.

Adolescent↗

PubMed1994

Ehlers-Danlos syndrome type VII: phenotype and genotype.

A patient suffering from a severe form of Ehlers-Danlos syndrome is presented (EDS type VII). The presence of bilateral congenital hip dislocation, generalized joint hypermobility and a soft hyperelastic skin with abnormal scarring suggested a specific collagen type I defect. SDS-PAGE analysis of collagens secreted into the medium of fibroblast cultures showed a retarded migration of more than half of the alpha 2(I) chains. CNBr peptide mapping of the HPLC-purified altered chain localized the mutant locus to the N-terminal region of the protein. cDNA analysis of the corresponding gene COL1A2 revealed, in addition to the expected collagen sequence, a transcript missing the entire exon 6. This exon encodes a major crosslinking site within collagen fibres as well as the N-propeptidase cleavage site. The skipping of exon 6 is caused by a splice site mutation substituting an A for a G at the first nucleotide of intron 6.

Base Sequence↗

PubMed1992

Lysyl hydroxylation in collagens from hyperplastic callus and embryonic bones.

Tissue from two patients with osteogenesis imperfecta suffering from a hyperplastic callus was studied. Although collagen type I from the compact bone and the skin and fibroblast cultures of these patients showed normal lysyl hydroxylation, collagen types I, II, III and V from the callus tissue were markedly overhydroxylated. Furthermore, the overhydroxylation of lysine residues covered almost equally the entire alpha 1 (I) collagen chain, as demonstrated by the analysis of individual CNBr-derived peptides. In addition, collagen type I was isolated from femoral compact bone of 33 individuals who died between the 16th week of gestational age and 22 years. Lysyl hydroxylation rapidly decreased in both collagen alpha 1 (I) and alpha 2 (I) chains during fetal development, and only little in the postnatal period. The transient increase in lysyl hydroxylation and the involvement of various collagen types in callus tissue argue for a regulatory mechanism that may operate in bone repair and during fetal development.

Adolescent↗

PubMed1992

Hyperplastic callus formation in osteogenesis imperfecta.

Osteogenesis imperfecta, an inherited disorder of connective tissues, affects roughly (OI) 4000 people in Germany (11). The main clinical symptoms are fragile bones, progressing skeletal deformities, generalized osteoporosis and short stature. Incidentally, the clinical manifestations can range from perinatal lethal forms to phenotypical normal adults. In many instances the underlying causes of the disease are mutations in gene coding for collagen I, the predominant protein in most connective tissues. Fracture healing is usually not impaired, although in a unique group of OI-patients, a tumor-like hyperplastic callus occurs with excessive deposition of extracellular matrix constituents. Biochemical analysis of the callus is reminiscent of bone from early stages of human development and normal fracture healing (e.g. collagen type composition, degree of posttranslational modification). This underlines that, besides collagen mutations, the regulation of collagen synthesis and their posttranslational processing might be disturbed in patients with hyperplastic callus formation.

Bony Callus↗