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BI6.1-3 | Extracellular Matrix — Part 2

Collagen Disorders — Genetic and Acquired

Collagen Disorders — Genetic vs Acquired

Disorder	Collagen Type Affected	Defect	Key Clinical Features	Inheritance
Osteogenesis Imperfecta (Type I OI)	Type I collagen	Reduced quantity or structural mutation of COL1A1/COL1A2	Brittle bones, blue sclerae, dentinogenesis imperfecta, hearing loss	Autosomal dominant
Classic Ehlers-Danlos (cEDS)	Type V collagen	COL5A1/COL5A2 mutations	Hyperextensible skin, joint hypermobility, easy bruising	Autosomal dominant
Vascular EDS (vEDS)	Type III collagen	COL3A1 mutations	Arterial/bowel/uterine rupture; translucent skin; life-threatening	Autosomal dominant
Alport Syndrome	Type IV collagen	COL4A5 mutation (alpha-5 chain)	Progressive nephritis, sensorineural deafness, anterior lenticonus	X-linked (most common)
Epidermolysis Bullosa (dystrophic)	Type VII collagen	COL7A1 mutations	Skin blistering below basement membrane, scarring	Autosomal dominant or recessive
Scurvy	All collagens (acquired)	Vitamin C deficiency → defective hydroxylation	Bleeding gums, perifollicular haemorrhage, poor wound healing	Acquired (dietary)

Osteogenesis Imperfecta (OI) — Brittle Bone Disease:
- Mutations in COL1A1 or COL1A2 genes (Type I collagen)
- Even a single Gly→X substitution in the Gly-X-Y repeat disrupts triple helix assembly → unstable collagen
- Features: recurrent fractures with minimal trauma, blue sclerae (thin scleral collagen lets choroid show through), hearing loss (ossicular chain damage), dentinogenesis imperfecta
- Severe forms: intrauterine fractures, death in neonatal period. Mild forms: "the child with lots of fractures" seen at district hospitals — must distinguish from non-accidental injury

Collagen Disorders — Genetic and Acquired — Multi-panel illustration of collagen disorders: OI types with clinical features, EDS variants (classic, vascular, kyphoscoliotic), scurvy mechanism and clinical signs, and Alport syndrome with GBM ultrastructure

Ehlers-Danlos Syndrome (EDS):
- Heterogeneous group of connective tissue disorders — 13 types
- Most common: defects in Type V collagen → Classic EDS (hyperextensible skin, joint hypermobility, easy bruising)
- Vascular EDS (Type IV): Type III collagen defect → risk of arterial/bowel/uterine rupture — life-threatening
- Joints in EDS feel "loose" because the ECM holding the joint capsule together is mechanically weak

Alport Syndrome:
- X-linked defect in Type IV collagen (COL4A5 gene) → defective glomerular basement membrane
- Features: haematuria from childhood, progressive nephritis, sensorineural deafness, ocular abnormalities

SELF-CHECK — : Collagen

In the collagen synthesis pathway, which cofactor is required by prolyl hydroxylase for the conversion of proline to hydroxyproline?

A. Vitamin D

B. Vitamin C (ascorbic acid)

C. Biotin

D. Pyridoxal phosphate (Vitamin B6)

Reveal Answer

Answer: B. Vitamin C (ascorbic acid)

A 2-year-old with recurrent bone fractures, blue sclerae, and hearing loss most likely has a mutation in which gene?

A. COL4A5 (Type IV collagen)

B. COL1A1 or COL1A2 (Type I collagen)

C. FBN1 (Fibrillin-1)

D. ADAMTS2 (Procollagen proteinase)

Reveal Answer

Answer: B. COL1A1 or COL1A2 (Type I collagen)

Glycosaminoglycans (GAGs) — Hydrated Scaffolds

Major Glycosaminoglycans (GAGs) — Structure and Function

GAG	Repeating Disaccharide	Key Feature	Tissue Distribution	Clinical Relevance
Hyaluronic acid	GlcNAc + Glucuronic acid	Not sulphated; no core protein; very long chains	Synovial fluid, vitreous humour, umbilical cord, skin	Intra-articular injections for osteoarthritis
Chondroitin sulphate	GalNAc + Glucuronic acid	Most abundant GAG; sulphated	Cartilage, bone, heart valves	Nutraceutical for joint health (evidence debated)
Heparan sulphate	GlcNAc + Glucuronic/Iduronic acid	Cell surface and basement membranes	Basement membranes, cell surfaces	Glomerular filtration barrier; growth factor co-receptor
Heparin	GlcNAc + Iduronic acid	Most highly sulphated GAG	Mast cell granules	Clinical anticoagulant (activates antithrombin III)
Keratan sulphate	GlcNAc + Galactose	No uronic acid; contains galactose instead	Cornea, cartilage, intervertebral disc	Corneal transparency; accumulated in Morquio syndrome

Glycosaminoglycans (GAGs) are long, unbranched polysaccharide chains built from repeating disaccharide units, usually containing:
- A hexosamine (glucosamine or galactosamine), often sulphated
- A uronic acid (glucuronic acid or iduronic acid)

Glycosaminoglycans (GAGs) — Hydrated Scaffolds — Multi-panel illustration of GAGs: general structure with repeating disaccharides and negative charges, five major GAG types with tissue locations, compressive resistance function in cartilage, and heparin-antithrombin anticoagulant mechanism

The dense negative charges (from sulphate and carboxylate groups) attract water and cations → GAGs form highly hydrated gels that resist compressive forces.

Major GAGs:

GAG	Key Feature	Location	Clinical Note
Hyaluronic acid	Unsulphated, very large	Joints, vitreous, umbilical cord	Viscosupplementation in OA
Chondroitin sulphate	Most abundant sulphated GAG	Cartilage, bone, skin	Decreases in osteoarthritis
Heparan sulphate	Anticoagulant-related	Basement membranes, cell surfaces	Binds growth factors
Heparin	Most sulphated	Mast cells, lung	Anticoagulant drug
Dermatan sulphate	Contains iduronic acid	Skin, blood vessels	MPS type I/II disorders
Keratan sulphate	Contains galactose instead of uronic acid	Cornea, cartilage	MPS IVA (Morquio)

Hyaluronic acid is unique: it has no sulphation, is not covalently linked to protein (free chain), and is the longest GAG chain (up to 25,000 disaccharides). It forms the backbone to which proteoglycans attach.

Proteoglycans and Mucopolysaccharidoses

Mucopolysaccharidoses (MPS) — Key Types

MPS Type	Name	Enzyme Deficiency	Accumulated GAG	Key Clinical Features	Inheritance
MPS I	Hurler syndrome (severe) / Scheie (mild)	Alpha-L-iduronidase	Dermatan sulphate, Heparan sulphate	Coarse facies, corneal clouding, hepatosplenomegaly, intellectual disability	Autosomal recessive
MPS II	Hunter syndrome	Iduronate-2-sulphatase	Dermatan sulphate, Heparan sulphate	Similar to Hurler but NO corneal clouding; milder	X-linked recessive (only X-linked MPS)
MPS III	Sanfilippo syndrome	Various (4 subtypes A-D)	Heparan sulphate	Severe neurodegeneration, behavioural problems, mild somatic features	Autosomal recessive
MPS IV	Morquio syndrome	N-acetylgalactosamine-6-sulphatase (A) / beta-galactosidase (B)	Keratan sulphate	Severe skeletal dysplasia, short stature, normal intelligence	Autosomal recessive

Proteoglycans = core protein + many GAG chains covalently attached. They are the shock absorbers of the ECM.

Proteoglycans and Mucopolysaccharidoses — Multi-panel illustration of proteoglycans and MPS: bottle-brush proteoglycan structure, aggrecan-hyaluronic acid aggregate in cartilage, lysosomal GAG degradation pathway, and three key MPS types (Hurler, Hunter, Morquio) with clinical features

Key proteoglycans:
- Aggrecan — the major cartilage proteoglycan; binds to hyaluronic acid via link proteins to form huge aggregates that resist compression in joints
- Perlecan — basement membrane proteoglycan; binds to type IV collagen and laminin
- Syndecan, Glypican — cell surface heparan sulphate proteoglycans; co-receptors for growth factors (FGF, VEGF)

Mucopolysaccharidoses (MPS) — lysosomal storage diseases caused by deficiency of specific lysosomal enzymes that degrade GAGs:
- MPS I (Hurler syndrome): α-L-iduronidase deficiency → accumulation of heparan + dermatan sulphate. Features: coarse facies, corneal clouding, hepatosplenomegaly, intellectual disability, cardiac valve disease. Autosomal recessive. Enzyme replacement therapy available.
- MPS II (Hunter syndrome): Iduronate-2-sulphatase deficiency (X-linked). Similar but milder; no corneal clouding.
- MPS IVA (Morquio): N-acetylgalactosamine-6-sulphatase deficiency → keratan sulphate accumulation. Skeletal dysplasia, atlantoaxial instability.

Diagnosis: urine GAG quantitation and typing, enzyme assay in leucocytes/fibroblasts, gene sequencing.

SELF-CHECK — : GAGs and Proteoglycans

A 2-year-old child has progressive coarse facies, cloudy corneas, hepatosplenomegaly, and joint stiffness. Urine shows elevated GAG excretion. Which enzyme deficiency is most likely?

A. Lysyl oxidase

B. α-L-iduronidase (Hurler syndrome)

C. Hyaluronidase

D. Prolyl hydroxylase

Reveal Answer

Answer: B. α-L-iduronidase (Hurler syndrome)