OSTEOGENESIS IMPERFECTA

COL1A1

Katelynn Weber

OSTEOGENESIS IMPERFECTA Characteristics 6/100,000

worldwide

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

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

COLLAGEN

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

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

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

OVERVIEW OF OI TYPESType Inheritanc

eSeverity Fractures Bone

DeformityStature DI Sclerae Hearing

LossI* AD Mild Few to 100 Uncommo

nNormal to short

Rare Blue 50%

II AD Perinatal Lethal

Multiple fractures of ribs, compression of long bones

Severe Severely short

Yes Dark Blue

-

III AD (rare recessive)

Severe Thin gracile bones, many fractures, popcorn epiphyses

Moderate to Severe

Very short

Yes Blue Frequent

IV* AD Moderate to Mild

Multiple Mild to Moderate

Variably short

Varies Normal to Grey

Some

V AD Moderate Multiple w/ hypertrophic fractures

Moderate Variable No Normal No

VI Uncertain Moderate Multiple Rhizomelic Shortening

Mildly short

No Normal No

VII AR Moderate Multiple Yes Mildly short

No Normal No

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

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

LITERATURE CITED Genetic Home Reference. Dentinogenesis

Imperfecta. 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. Osteogenesis Imperfecta: Brittle Bone Disease, OI. Retrieved from <https://ecampus.wvu.edu/webct/urw/tp3175580449031.lc3171995902051/displayURLForQM.dowebct?URLId=3175580617031&resetBreadcrumb=false&displayBCInsideFrame=true>