Collagen and Inherited Connective Tissue Diseases Structure and Evolution of the Magellanic Clouds

Home , Connective tissue

~7~~------NEVVSAN0VIEVVS------~N~A~ru~R~E~.v~<~'~~-m~-~2~7~c~~T~<~'B~ER~I~~3 some 17) but is clearly distinct from it. That Medical genetics it may be important in cartilage or bone formation was suggested by its strong hybridization to mRNA from a rat Collagen and inherited chondrosarcome (K.S.E. Cheah, Imperial Cancer Research Fund Laboratories, connective tissue diseases London). However, one parent in each from Bryan Sykes case was heterozygous for the deletion also and one parent at least had, in retrospect, COLLAGEN aficionados have long Studies on cultured fibroblasts (A. symptoms of other connective tissue cherished the idea that abnormalities in Nicholls, MRC Clinical Research Centre, disease. Irrelevant normal variants of the their protein lay behind the inherited London) had also led to the discovery of a gene were unlikely explanations since disorders of connective tissue. This patient who failed to incorporate pro-a2(1) about 400 other individuals did not have a complex mixture of clinical entities precursor chains into mature Type 1 deleted allele and the consensus was a pos presents with mechanical failure of tissues molecules. The symptoms were sible compound heterozygosity. like bone, gut and blood vessel walls, liga surprisingly mild, presumably because The same gene was used to illustrate ments, tendon and skin, often with dis compensatory formation of [a1(l)h trimer testing for causal mutations by segregation astrous results. Since collagen is the was an effective mechanical substitute. of single and multiple restriction site principal stress-bearing component of the Though pro- a2(I) levels were normal, S1 variants (B . Sykes) who showed how it susceptible tissues their belief is reasonable mapping revealed that the patient was could be excluded from causality in two but, largely owing to the complexity of the homozygous for a mutation at the 3' end of pedigrees of dominantly inherited Type I molecule, substantiation has till now been the gene corresponding to the C-propep disease. anecdotal, meagre and indirect. tide region, the effect of which was to block Most delegates left the meeting Obviously, collagen structural genes are incorporation (T. Pihlajamiena, Rutgers optimistic that the disease loci have been the prime candidates for the mutant loci Medical School, New Jersey). The parents identified and that the effort of many and gene probes now being used to test the were consanguinious and heterozygosity laboratories will one day be rewarded by a hypothesis are coming up with evidence to was confirmed. unified theory whereby collagen structural support it. It is too early to say whether the Much more perplexing was a 300 base gene mutations will explain first the bio understanding of collagen gene mutation pair deletion at the 3' end of the enigmatic chemistry, then the complex clinical and will ever reach the levels of sophistication a I (I) like gene found in four out of six peri genetic picture of these crippling diseases. seen with globin but an interdisciplinary natal lethal cases from widely different 0 meeting* on osteogenesis imperfecta, ethnic backgrounds (F.M. Pope, MRC Bryan Sykes is on the staff of the Nuffield heard the first encouraging reports that, Clinical Research Centre, London). This Department of Pathology, John Radcliffe one day, it might. gene, localised to chromosome 12, shares Hospital, University of Oxford, Oxford OX3 Collagen molecules consist of three sequence homology with al(l) (chromo- 9DU. collagen a-chains wound round one another in a regular helix. At least seven Astronomy distinct a-chains have been found (labelled a 1(I) through to a l(V), a 2(1) and a 2(V)) and combine in different types of collagen Structure and evolution of the molecules - types I and II, III being the major consitutents of connective tissues. Fibroblasts cultured from a perinatal Magellanic Clouds lethal case (Type II disease) synthesised an from Sidney van den Bergh and Klaas S. de Boer a 1(I) dimer disulphide bonded in a 1 CB6 towards the carboxy terminus of the helical RECENTLY over a hundred astronomers individual cluster stars. Recent multi region (B. Steinman, Universitats from the northern and southern hemi colour observations by L. Searle (Mt. Kinderklinik, Zurich). This defect spheres gathered to discuss the inter Wilson Observatory, Pasadena) are able to probably arose from a glycine-cysteine pretation of new observations of the order Cloud clusters by relative age while substitution and, since neither parent was Magellanic Clouds*. Since the last such colour-magnitude diagrams of stars within affected nor synthesized the abnormal meeting, in 1969, understanding of the some of these clusters provide an absolute chain, a new dominant mutation was pro Magellanic Clouds has been revolutionized age calibration. Such work has revealed posed. Any substitution for glycine in the by the completion of 4-m class telescopes in striking differences between the evo helix would prevent perfect packing, the southern hemisphere (Cerro Telolo lutionary histories of the Large Magellanic though it was conceded during discussion. Inter-American University and European Cloud and Small Magellanic Cloud on the (A. Miller, University of Oxford) that the Southern Observatory telescopes in Chile, one hand and the Galaxy on the other. degree of distortion is unknown. To and the Anglo-Australian telescope in Exceedingly old clusters, similar to explain the severity of the mutation of a Australia), by the development of highly galactic globular clusters, are found to be single allele it was suggested (B. Sykes, efficient panoramic detectors such as the relatively rare indicating that star and John Radcliffe Hospital, Oxford) that charge coupled device, and by observations cluster formation got off to a rather slow since each Type I molecule contained two from space. start in the Magellanic Clouds, contrasting a1(I) chains the gene product of one Because of their proximity the Large and with our Galaxy in which an enormous mutant allele could theoretically be Small Magellanic Cloud are crucial burst of star and cluster formation seems to incorporated into three-quarters of the stepping stones between our own Milky have taken place as the Milky Way system molecules. Taken together with the drastic Way system and the realm of distant collapsed from its gaseous proto-galactic effects of glycine substitution on helix galaxies. In particular the Clouds are the state. In the Galaxy this initial burst of star stability this may explain the high mutation only external galaxies in which it is possible formation resulted in the subsequent rate in many collagen diseases. to study both the integrated properties of production of vast numbers of supernovae, star clusters and the spectra and colours of which rapidly built up the heavy element abundance in the galactic interstellar gas. The Second lntt·rnational Symposium on