Discussion -- A 13 year-old girl with short stature


The COL1A1 and COL1A2 genes are similar in structure (51 and 52 exons, respectively). Although the COL1A1 gene is approximately half the size of COL1A2, both transcribe mRNAs of the same length. Each encodes an 'alpha' chain with a core triple helical domain composed of 338 uninterrupted repeats of Gly-X-Y tripeptide, usually with proline in X and either lysine or proline in Y, flanked by propeptides at both the amino and carboxy ends. Each of the 43 exons encoding the triple helical domain begins with a Gly codon and ends with a Y-position codon so that exon-skipping typically yields in frame transcripts. During chain synthesis and helix formation, some Y-position proline and lysine residues are hydroxylated, and lysine residues may be subsequently glycosylated. Glycine is essential at every third position of the chain because it is the only residue small enough to accommodate the sterically restricted inner aspect of the helix. Residues which substitute for glycine disrupt helix folding and propagation temporarily, exposing all three chains to hydroxylation and glycosylation.

There are two general classes of mutations of type I collagen that result in osteogenesis imperfecta (OI). Some lead to a quantitative defect of COL1A1, with synthesis of structurally normal type I procollagen at about half the normal amount (haploinsufficiency). Frameshifts or nonsense mutations often produce this milder form of OI due to nonsense-mediated decay of protein. Other mutations result in synthesis of collagen chains with structural abnormalities which typically interfere with proper assembly (dominant negative mutations). These variants change the protein sequence of the chains in the triple helical domain and lead to a wide phenotypic range, from lethal OI to mild-moderate type IV OI. Mutations causing the more clinically significant forms of OI demonstrate substitutions for one of the Glycine residues in the triple helical domain. Variants of splice donor or acceptor sites or those which activate cryptic sites affect mRNA and protein variably depending on whether structural mutations result abnormal protein that interferes with fibrillogenesis, collagen-matrix or collagen-cell interactions, or mineralization. There are 4 types of OI (I-IV) caused by structural mutations in the COL1A1 or COL1A2 genes, most commonly the former. All 4 are transmitted in an autosomal dominant fashion. Three other types (5, 6, and 7) have also been described and are under investigation.

Osteogenesis imperfecta is a group of disorders characterized by fractures with minimal trauma, short stature, blue sclera, dentinogenesis imperfecta, post-pubertal hearing loss, and in some cases bone deformities. OI type 1 is considered one of the milder forms of this disorder with fewer fractures; hearing loss is only present in ~50% of individuals. OI is inherited as an autosomal dominant disorder. This means that an affected individual has one copy of the abnormal gene and one normal gene. With each pregnancy, there is a 50% chance of passing along the abnormal gene to his or her offspring.

Deletion of a cytosine in one allele of the COL1A1 gene caused a frame-shift mutation in our patient with premature termination of transcription leading to haploinsufficiency. It could be argued this could produce a structural mutation, but the patient presents with a mild OI type I phenotype supporting a haploinsufficiency model in this case. Identification of a mutation in this family allows testing of other at-risk family members as well as prenatal diagnosis, if desired, in future pregnancies. Management of disease in this patient would include limitation of physical activities that lead to bone breakage, referral to orthopedics for continued management of bone problems, and annual DEXA scans to monitor the appearance of osteopenia.

Acknowledgment: DNA extraction from skin fibroblasts and sequencing were performed in the Collagen Diagnostic Laboratory at the University of Washington, Seattle, WA. Dr. Ulrike Schwarze, MD kindly supplied the sequencing figure. Dr. Suneeta Madan-Khetarpal, MD (Department of Medical Genetics, UPMC) was the primary clinician for this patient.


  1. Osteogenesis imperfecta foundation, www.oif.org
  2. MS. Kocher, F. Shapiro, Osteogenesis imperfecta, J Am Acad Orthop Surg 1998;6:225-236
  3. JC. Marini, PH. Byers, Consortium for Osteogenesis Imperfecta Mutations in the Helical Domain of Type I Collagen: Regions Rich in Lethal Mutations Align with Collagen Binding Sites for Integrins and Proteoglycans, Human Mutation 28(3)
  4. CA. Graham, AJM. Hill, DNA Sequencing Protocols, Humana Press, 2001

Contributed by Oana Mihaela Radu, MD and Jeffrey Kant, MD, PhD

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