Peter Byers, M.D.

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Email: pbyers@u.washington.edu

We are pursuing several lines of research: the characterization of mutations in type I collagen genes (COL1A1 and COL1A2) that give rise to forms of osteogenesis imperfecta (OI) and other disorders; the identification and characterization of mutations in the type III collagen gene (COL3A1), which give rise to Ehlers-Danlos syndrome type IV; characterization of mutations in other genes (e.g., COL5A1, COL5A2, PLOD1 and the -terminal procollagen protease) that result in other forms of connective tissue disorder; identification of proteins in the intracellular and extracellular processing pathways that identify abnormal collagen proteins; and the mechanisms of mRNA processing in collagen genes to predict the outcome of splice site mutations. In addition, we are searching for other genes that may give rise to phenotypes of osteogenesis imperfecta, and determining the rate and genetic basis of parental mosaicism for mutations in these genes.

The majority of mutations in the COL1Al and COLlA2 genes, which cause OI, results in substitution for glycines within the triple helix. Most of the remainder alter splice sites. Our studies of the mutations suggest that in some instances the order of exon splicing may determine the effects of splice mutations; as a consequence, we are studying the order of intron removal in such cell strains. One of the most puzzling aspects of OI has been the failure to identify mutations in all affected individuals. Using long amplification regions, we have noted low level splice defects in some such patients that result in the production of only a small amount of abnormal molecules due to the presence of 5-10% abnormal mRNA species as a consequence of mutations outside the canonical splice site sequences. However, it is clear that some mutations reside outside these two genes.

We have now characterized almost 250 mutations in our families with EDS type IV. These are more heavily weighted to point mutations that result in substitutions for glycine residues within the triple helix of the molecule than mutations that alter splice site integrity. Some of these mutations prohibit mRNA transport from the nucleus when introns that contain termination codons are included. These findings suggest that there is a link between splicing and nuclear recognition of premature termination codons that may be different from the recognition process that leads to cytoplasmic nonsense-codon-mediated mRNA decay. The mechanisms of recognition of these structures are being pursued. Similar approaches are being taken to understand disorders that result from several other genes involved in connective tissue biogenesis.

Dr. Byers is a Professor of Pathology and Medicine (Medical Genetics). He is PI of several grants, including “Molecular Basis of Osteogenesis Imperfecta” and “Identification and Expression of Skin Specific Genes,” and he has a project on "Collagen Gene Targeting with AAV Vectors."

• Pepin MG, Starman BJ, Atkinson MA, and Byers PH. Prenatal diagnosis of osteogenesis imperfecta by analysis of collagen synthesized by cells cultured from chorionic villus biopsies. Prenatal Diagnosis 17:559-570, 1997.
• Qi M, Byers PH. Constitutive skipping of an alternatively spliced exon 10 in the ATP7A gene abolishes Golgi localization of the Menkes protein and produces the occipital horn syndrome. Hum Molec Genet 7:465-469, 1998.
• Bateman JF, Greddi S, LamandeS, Byers P, Nasioulas S, Douglas J, Otway R, Kohonen-Corish M, Edkins E, Forrest S. Premature termination mutations and mRNA instability: cycloheximide protects the mutant mRNA and allows reliable and sensitive mutation detection by the protein truncation test. Hum Mutation 13:311-317, 1999.
• Raff ML, Craigen WJ, Smith LT, Keene DR, Byers PH. Partial COL1A2 gene duplication produces features of osteogenesis imperfecta and Ehlers-Danlos syndrome type VII. Human Genetics. Published online: 16 December 1999 DOI 10.1007/s004399900198
• Pepin M, Schwarze U, Superti-Furga A, Byers PH. Classical Ehlers-Danlos syndrome type IV: complications and early death due to mutations in the COL3A1 gene of type III collagen. N Engl J Med 342:673-680, 2000
• Byers PH. Disorders of collagen biosynthesis and structure. In: The Metabolic and Molecular Basis of Inherited Disease, 8th edition, CR Scriver, AL Beaudet, WS. Sly, D Valle, B Childs, B Vogelstein, eds. McGraw-Hill vol IV., 2001. p 5241.
• Schwarze U, Atkinson M, Hoffman GG, Greenspan DS, Byers PH. 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). Am J Hum Genet 66:1757-1765, 2000.
• Pace JM, Kuslich CD, Willing MC, Byers PH. Disruption of one intra-chain disulfide bond in the carboxyl-terminal propeptide of the proa1(I) chain of type I procollagen permits slow assembly and secretion of overmodified, but stable procollagen trimers and results in mild osteogenesis imperfecta. J Med Genet 38:443-9, 2001
• Byers PH. Killing the messenger: new insights into nonsense-mediated mRNA decay (critical review). J Clin Invest 109:3-6, 2002
• Byers PH, Cole WJ. Osteogenesis imperfecta. In: Connective Tissue and Its Heritable Disorders: Molecular, Genetic, and Medical Aspects. P Royce, B Steinmann, eds. 2nd Edition. New York:Wylie, in press.