Peter Byers, MD
Adjunct Professor, Oral Health Sciences
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 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 N-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 that cause OI result 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 gene.
We have now characterized almost 400 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 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 is being pursued.
Similar approaches are being taken to disorders which result from several other genes involved in connective tissue biogenesis.
- Persikov AV, Pillitteri RJ, Amin P, Schwarze U, Byers PH, Brodsky B (Oct 2004) Stability related bias in residues replacing glycines within the collagen triple helix (Gly-Xaa-Yaa) in inherited connective tissue disorders., Human Mutation, 24(4)330-7
- Byers PH (Jul 2004) Determination of the molecular basis of Marfan syndrome: a growth industry., The Journal of Clinical Investigation, 114(2)161-3
- Schwarze U, Hata R, McKusick VA, Shinkai H, Hoyme HE, Pyeritz RE, Byers PH (May 2004) Rare autosomal recessive cardiac valvular form of Ehlers-Danlos syndrome results from mutations in the COL1A2 gene that activate the nonsense-mediated RNA decay pathway., American Journal of Human Genetics, 74(5)917-30
- Kaiser FJ, Brega P, Raff ML, Byers PH, Gallati S, Kay TT, de Almeida S, Horsthemke B, Ludecke HJ (Feb 2004) Novel missense mutations in the TRPS1 transcription factor define the nuclear localization signal., European Journal of Human Genetics : Ejhg, 12(2)121-6
- Chamberlain JR, Schwarze U, Wang PR, Hirata RK, Hankenson KD, Pace JM, Underwood RA, Song KM, Sussman M, Byers PH, Russell DW (Feb 2004) Gene targeting in stem cells from individuals with osteogenesis imperfecta., Science, 303(5661)1198-201
- Palmeri S, Mari F, Meloni I, Malandrini A, Ariani F, Villanova M, Pompilio A, Schwarze U, Byers PH, Renieri A (Jun 2003) Neurological presentation of Ehlers-Danlos syndrome type IV in a family with parental mosaicism., Clinical Genetics, 63(6)510-5
- Pace JM, Corrado M, Missero C, Byers PH (Mar 2003) Identification, characterization and expression analysis of a new fibrillar collagen gene, COL27A1., Matrix Biology : Journal of the International Society for Matrix Biology, 22(1)3-14
- Takahara K, Schwarze U, Imamura Y, Hoffman GG, Toriello H, Smith LT, Byers PH, Greenspan DS (Sep 2002) Order of intron removal influences multiple splice outcomes, including a two-exon skip, in a COL5A1 acceptor-site mutation that results in abnormal pro-alpha1(V) N-propeptides and Ehlers-Danlos syndrome type I., American Journal of Human Genetics, 71(3)451-65
- Marlowe A, Pepin MG, Byers PH (Jun 2002) Testing for osteogenesis imperfecta in cases of suspected non-accidental injury., Journal of Medical Genetics, 39(6)382-6
- Chuman H, Trobe JD, Petty EM, Schwarze U, Pepin M, Byers PH, Deveikis JP (Jun 2002) Spontaneous direct carotid-cavernous fistula in Ehlers-Danlos syndrome type IV: two case reports and a review of the literature., Journal of Neuro-ophthalmology : the Official Journal of the North American Neuro-ophthalmology Society., 22(2)75-81