Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans
Joan C. Marini,Antonella Forlino,Antonella Forlino,Wayne A. Cabral,Aileen M. Barnes,James D. San Antonio,Sarah A. Milgrom,James C. Hyland,Jarmo Körkkö,Darwin J. Prockop,Anne De Paepe,Paul Coucke,Sofie Symoens,Francis H. Glorieux,Peter J. Roughley,Alan M. Lund,Kaija Kuurila-Svahn,Heini Hartikka,Daniel H. Cohn,Deborah Krakow,Monica Mottes,Ulrike Schwarze,Diana Chen,Kathleen Yang,Christine D Kuslich,James Troendle,Raymond Dalgleish,Peter H. Byers +27 more
TLDR
The data on genotype–phenotype relationships indicate that the two collagen chains play very different roles in matrix integrity and that phenotype depends on intracellular and extracellular events.Abstract:
Osteogenesis imperfecta (OI) is a generalized disorder of connective tissue characterized by fragile bones and easy susceptibility to fracture. Most cases of OI are caused by mutations in type I collagen. We have identified and assembled structural mutations in type I collagen genes (COL1A1 and COL1A2, encoding the proalpha1(I) and proalpha2(I) chains, respectively) that result in OI. Quantitative defects causing type I OI were not included. Of these 832 independent mutations, 682 result in substitution for glycine residues in the triple helical domain of the encoded protein and 150 alter splice sites. Distinct genotype-phenotype relationships emerge for each chain. One-third of the mutations that result in glycine substitutions in alpha1(I) are lethal, especially when the substituting residues are charged or have a branched side chain. Substitutions in the first 200 residues are nonlethal and have variable outcome thereafter, unrelated to folding or helix stability domains. Two exclusively lethal regions (helix positions 691-823 and 910-964) align with major ligand binding regions (MLBRs), suggesting crucial interactions of collagen monomers or fibrils with integrins, matrix metalloproteinases (MMPs), fibronectin, and cartilage oligomeric matrix protein (COMP). Mutations in COL1A2 are predominantly nonlethal (80%). Lethal substitutions are located in eight regularly spaced clusters along the chain, supporting a regional model. The lethal regions align with proteoglycan binding sites along the fibril, suggesting a role in fibril-matrix interactions. Recurrences at the same site in alpha2(I) are generally concordant for outcome, unlike alpha1(I). Splice site mutations comprise 20% of helical mutations identified in OI patients, and may lead to exon skipping, intron inclusion, or the activation of cryptic splice sites. Splice site mutations in COL1A1 are rarely lethal; they often lead to frameshifts and the mild type I phenotype. In alpha2(I), lethal exon skipping events are located in the carboxyl half of the chain. Our data on genotype-phenotype relationships indicate that the two collagen chains play very different roles in matrix integrity and that phenotype depends on intracellular and extracellular events.read more
Citations
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The Collagen Family
TL;DR: The collagen family comprises 28 members that contain at least one triple-helical domain and plays structural roles and contribute to mechanical properties, organization, and shape of tissues.
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Gibbon genome and the fast karyotype evolution of small apes
Lucia Carbone,R. Alan Harris,Sante Gnerre,Krishna R. Veeramah,Krishna R. Veeramah,Belen Lorente-Galdos,John Huddleston,John Huddleston,Thomas J. Meyer,Javier Herrero,Christian Roos,Bronwen Aken,Fabio Anaclerio,Nicoletta Archidiacono,Carl Baker,Daniel Barrell,Mark A. Batzer,Kathryn Beal,Antoine Blancher,Craig L. Bohrson,Markus Brameier,Michael S. Campbell,Oronzo Capozzi,Claudio Casola,Giorgia Chiatante,Andrew Cree,Annette Damert,Pieter J. de Jong,Laura Dumas,Marcos Fernandez-Callejo,Paul Flicek,Nina V. Fuchs,Gut I,Gut M,Matthew W. Hahn,Jessica Hernandez-Rodriguez,LaDeana W. Hillier,Robert Hubley,Bianca Ianc,Zsuzsanna Izsvák,Nina G. Jablonski,Laurel Johnstone,Anis Karimpour-Fard,Miriam K. Konkel,Dennis Kostka,Nathan H. Lazar,Sandra L. Lee,Lora Lewis,Yue Liu,Devin P. Locke,Swapan Mallick,Fernando L. Mendez,Fernando L. Mendez,Matthieu Muffato,Lynne V. Nazareth,Kimberly A. Nevonen,Majesta O'Bleness,Cornelia Ochis,Duncan T. Odom,Katherine S. Pollard,Javier Quilez,David Reich,Mariano Rocchi,Gerald G. Schumann,Stephen M. J. Searle,James M. Sikela,Gabriella Skollar,Arian F.A. Smit,Kemal Sonmez,Boudewijn F.H. Ten Hallers,Elizabeth Terhune,Gregg W.C. Thomas,Brygg Ullmer,Mario Ventura,Jerilyn A. Walker,Jeffrey D. Wall,Lutz Walter,Michelle C Ward,Michelle C Ward,Sarah J. Wheelan,Christopher W. Whelan,Christopher W. Whelan,Simon D. M. White,Larry J. Wilhelm,August E. Woerner,Mark Yandell,Baoli Zhu,Michael F. Hammer,Tomas Marques-Bonet,Tomas Marques-Bonet,Evan E. Eichler,Evan E. Eichler,Lucinda Fulton,Catrina Fronick,Donna M. Muzny,Wesley C. Warren,Kim C. Worley,Jeffrey Rogers,Richard K. Wilson,Richard A. Gibbs +99 more
TL;DR: The assembly and analysis of a northern white-cheeked gibbon genome is presented and the propensity for a gibbon-specific retrotransposon (LAVA) to insert into chromosome segregation genes and alter transcription by providing a premature termination site is described, suggesting a possible molecular mechanism for the genome plasticity of the gibbon lineage.
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TL;DR: The existence of several hot spots for ligand interactions on type I collagen and the existence of mutations associated with osteogenesis imperfecta and other disorders show apparently nonrandom distribution patterns within both the monomer and fibril, implying that mutation positions correlate with disease phenotype.
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