1. OsteogenesisImperfectaCOL1A1 Katelynn Weber

2. OsteogenesisImperfecta • Characteristics • 6/100,000 worldwide

3. Diagnosis • Child Abuse? • Clinical symptom evaluation, DNA and protein testing to confirm • Family history • Ultrasound and amniocentesis performed in utero • 90% of mutations in collagen 1 • Types II, III, IV often born with broken bones

4. COL1A1 • 17q21.33 • Osteogenesisimperfecta types I-IV • Ehlers-Danlos • Osteoporosis

5. COL1A1 • Collagen, type 1, alpha 1 • Type 1 collagen is the most abundant in the human body • Provides strength and support for cartilage, bone, tendon, skin, and sclera • COL1A1 codes for pro-α1(I) component of collagen

6. Collagen

7. Mutation • OI is most common result of COL1A1 mutations • Mildest for of OI results from reduced production of pro-α1(I) chains • More severe types (II, III, IV): • Deleted segments of DNA within COL1A1 • Altered aa sequence—replacement of glycine • AA substitutions alter C-terminus of protein • Abnormal collagen incorporated into bones causing severe forms of OI

8. Testing • To detect mutations that alter mRNA stability • Genomic DNA sequence analysis • Nonsense, missense, splice-site • Type IV (70-80%) • Complementary DNA sequence analysis • RNA derived from dermal fibroblasts; sometimes leukocytes • Missense, small insertions/deletions, exon-skipping • Types I (100%), II(98%), III (60-70%) • Mutations in most families are unique; only few recurrent mutations seen in more than one family

9. Inheritance • Autosomal Dominant • Types I-V • Autosomal Recessive • Type VII, sometimes III* • *Often indicates mutations in other genes (CRTAP or LEPRE1) • No history • Type II and III often present with no family history • Sporadic mutations in COL1A1 and COL1A2 • Children of proband have 50% chance of inheriting OI

10. Overview of OI Types

11. Treatments • Management of fractures: short-term, lightweight casts/splints/braces • PT and/or OT • Safe physical activity: swimming, walking, stationary cycling • Rodding (esp. children) • Reconstructive surgery, joint replacements

12. Therapies under investigation • Bisphosphonates (Pamidronate) • Decrease bone resorption to increase bone mass and strength • Mostly in severe types • Human growth hormone • Appears to improve linear growth rates and bone formation • Bone marrow transplant • Mesenchymal stem cells differentiate into normal osteoblasts

13. Literature Cited • Genetic Home Reference. DentinogenesisImperfecta. Reviewed November 2009. Retrieved from < http://ghr.nlm.nih.gov/condition/dentinogenesis-imperfecta> • Steiner, R.D., MD; M.G. Pepsin, MS, CGC; P.H. Byers, MD. Posted 28 January 2005. OsteogenesisImperfecta: Brittle Bone Disease, OI. Retrieved from <https://ecampus.wvu.edu/webct/urw/tp3175580449031.lc3171995902051/displayURLForQM.dowebct?URLId=3175580617031&resetBreadcrumb=false&displayBCInsideFrame=true>