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Several human diseases result from genetic defects of the collagen genes.
Additional defects in collagen structure may also arise from abnormal
posttranslational modification of collagen, or deficiency of cofactors needed by
the enzymes that carry out posttranslational modification of collagen.
Table 6.11. Selected Disorders in Collagen Biosynthesis and Structure
Disorder
Collagen Defect
Osteogenesis
imperfecta 1
Osteogenesis
imperfecta 2
Decreased synthesis of
type I
Point mutations and exon
rearrangements in triple
helical regions
EhlersDanlos IV Poor secretion, premature
degradation of type III
collagen
EhlersDanlos VI Decreased hydroxylysine
in types I and III collagen
EhlersDanlos VII Type I procollagen
accumulation: N-terminal
propeptide not cleaved
Cutis laxa
Decreased crosslinking
(occipital horn
due to poor Cu
syndrome)
distribution
Clinical Manifestations
Long bone fractures prior to
puberty
Perinatal lethality; malformed and
soft, fragile bones
Translucent skin, easy bruising,
arterial and colon rupture
Hyperextensive skin, joint
hypermobility
Joint hypermobility and
dislocation
Lax, soft skin; occipital horn
formation in adolescents
problems arise from arterial rupture, intestinal perforation, and rupture of the
uterus during pregnancy or labor. Surgical repair is difficult because of tissue
fragility. The basic defects in type IV EhlersDanlos are due to changes in the
primary structure of type III chains. These arise from point mutations that result in
replacement of glycine residues and thus disruption of the collagen triple helix,
and from exon-skipping, which shortens the polypeptide and can result in
inefficient secretion and decreased thermal stability of the collagen and in
abnormal formation of type III collagen fibrils. In some cases type III collagen is
accumulated in the rough ER, overmodified, and degraded very slowly.
In type VI EhlersDanlos syndrome lysyl hydroxylase is deficient. As a result
type I and III collagens in skin are synthesized with decreased hydroxylysine
content, and subsequent cross-linking of collagen fibrils is less stable. Some
cross-linking between lysine and allysine occurs but these are not as stable and
do not mature as readily as do hydroxylysine-containing cross-links. In addition,
carbohydrate is transferred to the hydroxylysine residues but the function of this
carbohydrate is unknown. The clinical features include marked hyperextensibility
of the skin and joints, poor wound healing, and musculoskeletal deformities.
Some patients with this form of EhlersDanlos syndrome have a mutant form of
lysyl hydroxylase with a higher Michaelis constant for ascorbic acid than the
normal enzyme. Accordingly, they respond to high doses of ascorbic acid.
In EhlersDanlos syndrome type VII, skin bruises easily and is
hyperextensible, but the major manifestations are dislocations of major joints,
such as hips and knees. Laxity of ligaments is caused by incomplete removal of
the amino-terminal propeptide of the procollagen chains. One variant of the
disease results from deficiency of procollagen N-protease. A similar deficiency
occurs in the autosomal recessive disease called dermatosparaxis of cattle,
sheep, and cats, in which skin fragility is so extreme as to be lethal. In other
variants the pro1(I) and pro2(I) chains lack amino acids at the cleavage site
because of skipping of one exon in the genes. This prevents normal cleavage by
procollagen N-protease.
In type IX EhlersDanlos syndrome and in Menkes' kinky hair syndrome
there is thought to be a deficiency in lysyl amino oxidase activity. In type IX
EhlersDanlos syndrome there are consequent cross-linking defects manifested
in lax, soft skin and in the appearance during adolescence of bony occipital
horns. Copper-deficient animals have deficient cross-linking of elastin and
collagen, apparently because of the requirement for cuprous ion by lysyl amino
oxidase. In Menkes' kinky hair syndrome there is a defect in intracellular copper
transport that results in low activity of lysyl oxidase, and in occipital horn
syndrome there is a defect in intracellular copper distribution. A woman taking
high doses of the copper-chelating drug, d-penicillamine, gave birth to an infant
with an acquired EhlersDanlos-like syndrome, which subsequently cleared. Side
effects of d-penicillamine therapy include poor wound healing and
hyperextensible skin.
Scurvy
Most animals, but not humans, can synthesize ascorbic acid (vitamin C). Scurvy
results from dietary deficiency of ascorbic acid. Among other problems, ascorbic
acid deficiency causes decreased hydroxy-proline synthesis because prolyl
hydroxylase requires ascorbic acid. Hydroxyproline provides additional hydrogenbonding atoms that stabilize the collagen triple helix. Collagen containing
insufficient hydroxyproline loses temperature stability and is significantly less
stable than normal collagen at body temperature. The resultant clinical
manifestations are distinctive and understandable: suppression of the orderly
growth process of bone in children, poor wound healing, and increased capillary
fragility with resultant hemorrhage, particularly in the skin. Severe ascorbic acid
deficiency leads secondarily to a decreased rate of procollagen synthesis.
ALPORT SYNDROME
(Hereditary Hematuric Nephritis)
CASE REPORT
Patient: 19-year old male with Alport Syndrome
Symptoms: hematuria, proteinuria, and kidney failure
Family history: mother and sister have persistent microscopic hematuria without
renal complications
Case history:
Age of the patient Symptoms/procedure
1-year
otitis, microscopic hematuria
2-3-year
persistent hematuria
4-year
slight sensorineural hearing loss at high frequencies (60008000 Hz)
8-year
diffuse proliferative changes in the glomeruli; thinning,
thickening and lamellation of the glomerular basement
membrane (GMB) - by kidney biopsy and electron- or lightmicroscopy
received hearing aid
12-year
bilateral, significant hearing loss
18-year
persistent hematuria and proteinuria
development of kidney failure and high blood pressure
19-year
condition worsened
DNA analysis for the patient:
COL4A5 point mutation (one of the genes for collagen type IV)
Change of C T
Resulted in amino acid change from Arg Stop codon
Consequence is a truncated, non-functional 5(IV) polypeptide
chain and type IV collagen in the basement membrane
DNA analysis for the mother and sister: they are heterozygous for this mutation
Laboratory analysis at 18- and 19-year of age:
Normal
Hemoglobin
Hematocrit
Blood erythrocyte
Serum albumin
S-Calcium
FS-phosphorus
S-creatinin
FS-urea
FS-cholesterol
FS-triglycerides
Blood pH
Blood base access
135-165 g/l
0.4-0.54
4.5-6.5 E12/l
35-49 g/l
2.2-2.7 mmol/l
0.8-1.5 mmol/l
60-115 mol/l
1.7-8.3 mmol/l
3-7 mmol/l
0.4-1.7 mmol/l
7.35-7.42
-2.5+2.5
18-y
19-y
118
0.34
1
21-30
0.98
1.77
320
16
8.1
4.52
7.27
-7.1
90
0.27
0.27
28
2.19
1.63
586
17.4
7.6
3.08
7.25
-11.2
KIDNEY
Function of kidney: preservation of the volume and the composition of the
extracellular (and intracellular) fluid.
With day-to-day variations in amount and composition of food and fluids,
preservation of the internal environment requires the continuous excretion
of these substances (or their by-products) in amounts that balance
precisely the quantities acquired by ingestion and metabolic
transformation.
Nephrons: Ultrafiltration ~ 180 l fluid/day by glomerular capillaries
Re-absorption of more than 99% of filtrate by renal tubules
Urine ~ 1.5 l/day
The filtering unit of kidney nephron. Components: glomerulus, Bowmans capsule, tubules.
Gene
COL4A2
COL4A4
COL4A6
Protein
1(IV)
3(IV)
5(IV)
Gene
COL4A1
COL4A3
COL4A5
Chr
13
2
X
10
Tissue localization of -chains (Table I, Kashtan, J.Am.Soc.Nephrol. 9:17361750. 1998): (FYI only)
1 and 2 are found in all BMs 1(IV)2 2(IV)
3 and 4 are more restricted
5 is expressed where 3 and 4 are and at other location
(heterotrimers)
6 is expressed if 5 is there
Antibodies to these -chains can help in diagnosing AS
11
12
DIAGNOSIS OF AS:
Progressive hematuric hereditary nephritis caused by mutation in type IV
collagen genes.
Phenotypically heterogeneous, symptoms depend on chromosomal location of
the defect and gender.
Usual criteria:
1. familial history (however, de novo mutations are noted in 15% of
cases)
2. hearing loss
3. ocular lesions
4. GBM abnormalities
Characteristic feature of GMB in AS:
Thickening of the GBM with transformation of the lamina densa into a
heterogeneous network of membranous strands.
Starts with thinning of the GBM, then splitting and thickening follows.
For the compensation of the lack of 3,4,5(IV) chains 1(IV), 2(IV) chains
and types V and VI collagens accumulate in GBM. These proteins spread
from their normal sub-endothelial location and occupy the whole GBM. As
AS glomeruli undergo sclerosis, 1(IV) and 2(IV) chains disappear but type
V and VI collagen accumulate.
Clinical definition: 4 of the 10 criteria must be satisfied, ultimately DNA analysis is
required (see figure, FYI only)
Therapy: none
In end-stage renal disease hemodialysis and kidney transplantation are
considered.
(note: anti-GBM nephritis can occur because of the lack of 5 immune
tolerance)
Gene therapy introduction of normal cDNA for 5(IV) to glomerular cells is in
experimental stage
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