1. Collagen structural defects
Dr.S.Chakravarty ,MBBS, MD

2. Diseases associated with Collagen structure
Scurvy
Osteogenesis Imperfecta
Ehler Danlos syndrome
Alport syndrome
Fuch’s dystrophy
Menke’s disease
Goodpasture syndrome

3. Scurvy

4. 2/3 rd of Vasco di Gama’s sailors had died due to Scurvy by the time he reached India.

5. Scurvy Barlow’s disease. Vitamin C is required for collagen synthesis
Hydroxylation of lysine and proline.
Lysyl and prolyl hydroxylase.
Important for stabilizing pro-collagen peptides.
Bleeding gums, joints-hemarthrosis, fragile blood vessels.

6. Osteogenesis Imperfecta
Brittle bone disease
Lobstein disease.
Type-1 collagen disease.

8. Osteogenesis Imperfecta
Autosomal Dominant disease.
Substitution of Glycine with bulkier aminoacids.
Larger side chains-Steric hinderance between the chains causing bulges
Body hydrolyses the improper collagen structure.

9. Signs and Symptoms
Blue sclerae, short stature, hearing loss, respiratory problems, dentiogenesis imperfecta
Brittle bone – multiple fractures on mild pressure

10. Stress state within collagen fibrils is altered at the locations of mutations

11. MULTIPLE FRACTURES

12. 8 TYPES OF OI Type Description Gene OMIM Mode of Inheritance I mild
Null COL1A1 allele
(IA), (IB)
autosomal dominant, 60% de novo [5] II
severe and usually lethal in the perinatal period
COL1A1, COL1A2,
(IIA), (IIB)
autosomal dominant, ~100% de novo [5]
III
considered progressive and deforming
COL1A1, COL1A2
259420 IV
deforming, but with normal scleras
166220 V
shares the same clinical features of IV, but has unique histologic findings ("mesh-like")
unknown
610967
autosomal dominant [5] VI
shares the same clinical features of IV, but has unique histologic findings ("fish scale")
610968
unknown [5]
VII
associated with cartilage associated protein
CRTAP
610682
autosomal recessive [5]
VIII
severe to lethal, associated with the protein leprecan
LEPRE1
610915
autosomal recessive

13. dentiogenesis imperfecta Brittle bone –
Type 1 – mildest form
Type 2 – lethal
Type 4 – no blue sclera
(the blue-gray color of the sclera is due to the underlying choroidal veins which show through the thin sclera)
Blue sclerae,
short stature,
hearing loss,
respiratory problems,
dentiogenesis imperfecta
Brittle bone –
multiple fractures on mild pressure

14. Ehler Danlos Syndrome
Cutis hyperplastica.

17. Ehler Danlos syndrome:
Group of genetic defects involving synthesis of collagen(COL5A, COL 3A) and associated proteins.
Collagen in connective tissue helps tissues to resist deformation (decreases its elasticity) – due to defect in collagen synthesis  hyperelastic

18. Classification: Hypermobility – tenascin gene Type 3 defect
This gene encodes a member of the tenascin family of extracellular matrix glycoproteins.Here collagen density is also reduced .
Classical – (type1 and 2) affects collagen type 5.
Vascular- type 3 collagen

19. Clinical features: Hypermobility of the joints Hyperelastic skin
Fragile tissue – easy bruising, scaring, wounding.

20. Alport syndrome: (Hereditary Nephritis )
X-linked recessive.
May be Autosomal recessive.
Glomerulonephritis,
Deafness
Hematuria.
Alport syndrome is caused by mutations in COL4A(n)
COL4A3, COL4A4, and COL4A5, collagen biosynthesis genes
Type 4 collagen defect.
IMPROPER Basement membrane – basket weave appearance
Sensorineural hearing loss.

21. Fuchs Corneal dystrophy
Degenerative disorder of corneal endothelium.
Defect in collagen –type 8.
Autosomal dominant
Fuchs' endothelial dystrophy, is a slowly progressing corneal disease that usually affects both eyes
Females>Male

22. Fuchs Corneal dystrophy
Blurred vision that will gradually clear during the day
Later stages - Swelling will remain constant and reduce vision throughout the day.
CORNEAL OEDEMA and LOSS of VISION

23. Menkes disease Kinky hair disease or menke kinky hair syndrome
Mutations in the ATP7A gene on chromosome Xq13
X- linked recessive

24. Menke’s disease
Copper accumulates in some tissues, such as the small intestine and kidneys
The decreased supply of copper reduce the activity of numerous copper-containing enzymes - lysyl oxidase.
coarse hair, growth failure, and deterioration of the nervous system

25. Goodpasture syndrome:
Anti-glomerular basement membrane antibody disease.
Auto-immune reaction against goodpasture antigen.
Glomerulonephritis and hemorrhage of the lungs.

26. Goodpasture syndrome:
Sometimes this disorder is triggered by a viral respiratory infection or by breathing in hydrocarbon solvents-
Type II hypersensitivity reaction to Goodpasture’s antigens on the basement membrane of lungs and kidney.
Produces IgG antibodies against Alpha-3 chain of 
Type IV collagen.
clinical features- cough, hemoptysis, Hematuria, Renal failure

27. Marfan syndrome : Autosomal dominant disease
Mutation in geneFBN1 encoding for fibrillin protein.
Fibrillin also regulates TGF-β. Defect causes abnormalities in lungs, aorta and heart valves.
Lens dislocation – supero temporal

28. Clinical features: Arachnodactyly – long and slender fingers.
Uppersegment longer than lower segment.
Scoliosis and pectus excavatum/carinatum.
Mitral valve prolapse / aortic regurgitation/ aortic aneurysms.
Lungs – spontaneous pneumothorax.

29. Alpha -1 antitrypsin deficiency
Autosomal co-dominant/ recessive
SERPINA1 gene –mutation
Either decrease or abnormal synthesis.
Allelles – MM-Normal
SS- Intermediate
ZZ- worst.
Neutrophil elastase – damages lungs.

30. Clinical features: Development of emphysema
Clinical features: difficulty in breathing, wheezing, shortness of breath, respiratory infections, barrel shaped chest.
development of Cirrhosis:
jaundice, portal hypertension – swollen abdomen, swollen limbs.

31. Pseudoxantoma elasticum
Pseudoxanthoma elasticum is a progressive disorder that is characterized by the accumulation of deposits of calcium and other minerals (mineralization) in elastic fibers, which are a component of connective tissue.
Autosomal recessive
ABCC6 gene
Chromosome 16
Grönblad–Strandberg syndrome
Angioid streaks

32. Features
fragmentation and mineralization of elastic fibers in some tissues.
Small, yellowish papular lesions –axillae, neck, groin, elbow, knee.
dimpling of the Bruch membrane - peau d'orange appearance.
Angioid streaks – calcification of blood vessels.
CAD and MI

33. MCQ 1
A 4 month old infant who failed to grow and appeared to be mentally retarded was brought to the clinic for testing .The physician noted that the infant had abnormally kinky and hypopigmented hair. Arteriograms showed tortuosity of the major arteries.
Blood test showed that the infant had low serum ceruloplasmin and only 10% of normal copper levels.
What is the clinical disorder?
1)Osteogenesis imperfecta
2)Scurvy
3) Menke’s disease
4)Blue baby syndrome
5)Phenylketonuria
Menke’s disease

35. EXTRA CELLULAR CLEAVAGE

36. Marfan’s Syndrome