Osteogenesis imperfecta

From Iusmgenetics

Contents 1 Osteogenesis imperfecta 1.1 General background information 1.2 Mode of inheritance 1.3 Single important gene 1.4 Etiology 1.5 Pathogenesis 1.6 Phenotypic information 1.7 Diagnosis 1.8 Treatment 1.9 Recent research 1.10 5 important facts 1.11 Not to be confused with 1.12 Questions and answers

Osteogenesis imperfecta

• Think haploinsufficiency and dominant-negative effect.

General background information

• 4 types: 1-4
  • Type 1: most common, 1/15K
  • Type 2: most severe
  • Type 3:
  • Type 4:

Mode of inheritance

• Type 2: most are due to de novo mutation as it is severe
• Can demonstrate locus heterogeneity by mutations in either proalpha1 or proalpha2 (both of which get integrated into a collagen fibril).
  • Two alpha1 fibers + one alpha2 fiber.
• Type 1 can be passed to next generation

Single important gene

Etiology

• When an allele is broken, it can either produce NO product (which--in OI--results in haploinsufficiency) or bad product (which--in OI--results in dominant-negative effect).
  • Haploinsufficiency: when one allele is broken, so there just isn't enough alpha chain and therefore not enough collagen.
  • Dominant-negative effect: one allele produces bad product (alpha chains), the other produces good product (alpha chains), and then they are put together to produce a bad collagen fiber.
    • Dominant-negative will have a 3:1 ratio of abnormal to normal collagen fibrils (if one allele of the 2 alleles producing alpha1 chain is broken) because there are two alpha1 and one alpha2 chains in a collagen fiber.
• Type 1:
  • Mutation is a null mutation in the promotor of the alpha1 chain
  • Mutation does not affect the product but decreases the amount of alpha1 chain available: haploinsufficiency.
  • Results in decreased (though normal) type 1 fibrils
• Types 2, 3, 4:
  • Mutation is in the alpha1 or alpha2 chains
  • Mutation causes deformed chain.
  • Deformed chain gets integrated into triple helix.
  • Triple helix with deformed chain gets post-translationally modified on amino terminal.
  • Modified helix gets degraded, not secreted (as it should).
  • Results in decreased amount of collagen fibrils.
  • Has a dominant negative affect because even though only one allele is mutated, it causes destruction of even the wildtype chains (because they get put in the same triple helix and then that helix is degraded).
    • Also called "protein suicide".
    • Occurs with multisubunit, complex molecules.
• Type 2:

Pathogenesis

• Normal collagen is made up of 2 alpha1 chains and 1 alpha2 chain.
• Normal collage has it's amino and carboxy terminal trimmed by proteases.
• This trimmed triple helix of alpha1/2 fibers results in collagen fibrils which then get mineralized into bone.

Phenotypic information

• Severity (ish): 2 > 3 = 1 < 4
• Type 1: brittle bones, tendency for fractures, fractures heal without deformity, blue sclerae, deafness
• Type 2: most severe, perinatal lethal, many perinatal fractures, dark sclerae
• Type 3: some perinatal fractures, progressive deformity, growth retardation, some blue sclerae
• Type 4: tendency for fractures, normal sclerae

Diagnosis

• Xrays, clinical presentation

Treatment

Recent research

5 important facts

Not to be confused with

Questions and answers