Which of the following is the most common cause of hereditary osteogenesis imperfecta (OI)?

Question

Accepted Answer

B. Mutations in COL1A1 gene encoding pro-α1(I) chain of type I collagen. ## Osteogenesis Imperfecta: Genetic Basis

**Key Point:** Approximately 90% of autosomal dominant OI cases result from mutations in COL1A1 or COL1A2 genes, which encode the two chains of type I collagen (pro-α1(I) and pro-α2(I)).

## Type I Collagen and Its Role in Bone

**High-Yield:** Type I collagen comprises ~90% of the organic matrix of bone. It provides:
- Tensile strength and flexibility
- Scaffold for mineralization
- Cross-linking through lysine and hydroxylysine residues

Defective type I collagen → weak, brittle bone → pathological fractures.

## Osteogenesis Imperfecta Classification (Sillence)

| Type | Severity | Gene | Inheritance | Key Features |
|------|----------|------|-------------|---------------|
| I | Mild | COL1A1/A2 | AD | Blue sclerae, normal stature, few fractures |
| II | Perinatal lethal | COL1A1/A2 | AD | Severe deformities, intrauterine fractures, death in infancy |
| III | Severe | COL1A1/A2 | AD/AR | Progressive deformity, short stature, many fractures |
| IV | Moderate | COL1A1/A2 | AD | Normal sclerae, variable severity |

**Mnemonic: BLUE SCLERAE** — Blue sclera is pathognomonic for OI types I and III due to thinned sclera allowing visualization of underlying choroid.

## Pathophysiology of Type I Collagen Mutations

1. **Point mutations** in COL1A1/A2 → substitution of glycine (Gly-X-Y repeat) → disrupted triple helix
2. **Null mutations** → reduced collagen quantity
3. **Structural mutations** → abnormal cross-linking and mineralization

**Clinical Pearl:** Even heterozygous mutations (one mutant allele) cause significant phenotype because type I collagen is a heterotrimer (α1₂α2). A single mutant chain can disrupt the entire molecule (dominant negative effect).

**Warning:** Do not confuse OI with rickets (vitamin D deficiency) — rickets shows biochemical abnormalities (↓ calcium, ↑ phosphate, ↑ ALP) and responds to vitamin D; OI has normal biochemistry and is genetic.

[cite:Robbins 10e Ch 5; Harrison 21e Ch 411]

Answer

A. Mutations in COL4A3 gene encoding pro-α3(IV) chain of type IV collagen

Answer

C. Mutations in COL3A1 gene encoding pro-α1(III) chain of type III collagen

Answer

D. Mutations in PLOD1 gene encoding lysyl hydroxylase enzyme

Which of the following is the most common cause of hereditary osteogenesis imperfecta (OI)?

Explanation

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