O STEOGENESIS I MPERFECTA COL1A1 Katelynn Weber

O STEOGENESIS I MPERFECTA Characteristics 6/100,000 worldwide

D IAGNOSIS 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

COL1A1 17q21.33 Osteogenesis imperfecta types I-IV Ehlers-Danlos Osteoporosis

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

C OLLAGEN

M UTATION 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

T ESTING 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

I NHERITANCE 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

O VERVIEW OF OI T YPES TypeInheritanceSeverityFracturesBone Deformity StatureDIScleraeHearing Loss I*ADMildFew to 100UncommonNormal to short RareBlue50% IIADPerinatal Lethal Multiple fractures of ribs, compression of long bones SevereSeverely short YesDark Blue - IIIAD (rare recessive) SevereThin gracile bones, many fractures, popcorn epiphyses Moderate to Severe Very short YesBlueFrequent IV*ADModerate to Mild MultipleMild to Moderate Variably short VariesNormal to Grey Some VADModerateMultiple w/ hypertrophic fractures ModerateVariableNoNormalNo VIUncertainModerateMultipleRhizomelic Shortening Mildly short NoNormalNo VIIARModerateMultipleYesMildly short NoNormalNo

T REATMENTS 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

T HERAPIES 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

L ITERATURE C ITED Genetic Home Reference. Dentinogenesis Imperfecta. Reviewed November Retrieved from Steiner, R.D., MD; M.G. Pepsin, MS, CGC; P.H. Byers, MD. Posted 28 January Osteogenesis Imperfecta: Brittle Bone Disease, OI. Retrieved from