2. Cell membrane
• Membranes are complex structures composed
of lipids, carbohydrates, and proteins
• The basic structure of all membranes is the
lipid bilayer
• Proteins in membranes can be classified as
receptors, transporters, ion channels,
enzymes, and structural components
4. Biomedical importance of
membranes
• Separate one cell from another and thus
permit cellular individuality
• Has selective permeabilities (provided mainly
by channels and pumps for ions and
substrates) and acts as a barrier
• Plasma membrane plays key roles in cell-cell
interactions and in transmembrane signaling
• Membranes also form specialized
compartments (organelles) within the cell
5. Cont…
• Function as integral elements in excitation-
response coupling
• Provide sites of energy transduction, such as
in photosynthesis and oxidative
phosphorylation
• Normal cellular function depends on normal
membranes. Specific deficiencies or
alterations of certain membrane components
lead to a variety of diseases
6. Membrane diseases
• Members of all of these classes are often
glycosylated, so that mutations affecting this
process may alter their function
• These disorders mainly reflect mutations in
proteins of the plasma membrane, with one
affecting lysosomal function (Inclusion-Cell (I-
Cell) Disease/ Mucolipidosis Type II)
7. Cont…
• Membrane proteins can also be affected by
conditions other than mutations such as
formation of auto antibodies to acetylcholine
receptor in skeletal muscles causes
myasthenia gravis
• Ischemia can quickly affect the integrity of
various ion channels in membranes.
Abnormalities of membrane constituents
other than proteins can also be harmful
8. Cont…
• Mutations in genes encoding proteins in other
membranes can also have harmful
consequences. Eg, mutations in genes
encoding mitochondrial membrane proteins
involved in oxidative phosphorylation can
cause neurologic and other problems (eg,
Leber’s hereditary optic neuropathy; LHON –
loss of central vision)
9. Some diseases of the membranes
• Cystic fibrosis
• Red cell membrane defects
• Achondroplasia
• Congenital long QT syndrome
• Wilson disease
• I-cell disease
• Leber’s hereditary optic neuropathy
10. Cystic fibrosis
• It is a recessive genetic disorder that involves
multiple organ systems but chiefly results in
chronic respiratory infections, pancreatic enzyme
insufficiency, and associated complications
• End-stage lung disease is the principal cause of
death
• Caused by mutation on chromosome 7, encoding
a protein of 1480 amino acids, named cystic
fibrosis trans-membrane regulator (CFTR) which
is a cyclic AMP-regulated Cl− channel
11. Cont…
• The commonest mutation (~70%) is deletion
of three bases, resulting in loss of residue 508,
a phenylalanine. Leading to defective protein
maturation and early degradation
• However, more than 900 other mutations
have been identified
• Incidence 1:3,400 in causians
12. Cont…
• These mutations affect CFTR in at least four ways:
1) Its amount is reduced
2) It may be susceptible to misfolding and retention
within the ER or Golgi apparatus
3) Mutations in the nucleotide-binding domains
may affect the ability of the Cl− channel to open,
an event affected by ATP
4) The mutations may also reduce the rate of ion
flow through a channel, generating less of a Cl−
current
13. Pathophysiology
• Defective CFTR results in decreased secretion of
chloride and increased reabsorption of sodium
and water across epithelial cells
• Resulting in reduced epithelial lining fluid and
decreased hydration of mucus making mucus that
is stickier to bacteria, which promotes infection
and inflammation
• Secretions in the respiratory tract, pancreas, GI
tract, sweat glands, and other exocrine tissues
have increased viscosity, which makes them
difficult to clear
15. Clinical features
Respiratory signs
and symptoms
• A persistent cough
that produces thick
sputum
• Wheezing
• Breathlessness
• Exercise
intolerance
• Repeated lung
infections
• Inflamed nasal
passages or a stuffy
nose
Digestive signs
and symptoms
• Foul-smelling, greasy
stools
• Poor weight gain and
growth
• Intestinal blockage,
particularly in
newborns (meconium
ileus)
• cystic fibrosis-related
diabetes mellitus
(CFRDM)
• Severe
constipation/diarrhoea
Reproductive
system
• Infertility.
Congenital bilateral
absence of the vas
deferens (CBAVD),
a condition in
which the vas
deferens are
blocked by mucus
and do not develop
properly
• Thick cervical
mucus plug
16. Diagnosis of CF
• Requirements for dx include either positive
genetic testing or positive sweat chloride test
>60 mmol/L and 1 of the following:
i. Typical COPD
ii. Documented exocrine pancreatic
insufficiency
iii. Positive family history (usually an affected
sibling)
17. Management
• No definitive treatment
• Maintaining lung function by controlling
respiratory infection and clearing airways of
mucus (abx, mucolytics eg; acetylcistein,
expectorants eg;hypertonic saline, inhaled
bronchodilators, chest physical therapy and
postural drainage)
• Nutritional therapy (ie, enzyme supplements,
multivitamin) to maintain adequate growth
• Gene therapy to restore the activity of CFTR
20. Red cell membrane defect
• Hereditary spherocytosis
• Hereditary elliptocytosis
• Hereditary stomatocytosis
• Pyropoikilocytosis.
In each abnormalities of the red cell membrane
result in hemolysis
21. Hereditary spherocytosis (HS)
• HS is an AD familial hemolytic disorder associated
with a variety of mutations that lead to defects in
RBC membrane proteins
• It is the most common inherited abnormality of
the red blood cell membranes
• The morphologic hallmark of HS is the
microspherocyte, which is caused by loss of RBC
membrane surface area and has abnormal
osmotic fragility in vitro
• Incidence 1:5000
22. Abnormalities in RBC membrane
proteins in HS
I. Spectrin deficiency alone
II. Combined spectrin and ankyrin deficiency
III. Band 3 deficiency
IV. Protein 4.2 defects
• Spectrin; a cytoskeletal protein
• Ankyrin; linker proteins between the spectrin-
actin based cytoskeleton and integral
membrane proteins
23. Cont…
• Spectrin is made up of alpha-beta dimers
• Mutations of alpha-spectrin are associated with
recessive forms of HS, whereas mutations of
beta-spectrin occur in autosomal dominant
forms of HS
• Translocation of xsome 8 or deletion of the short
arm of xsome 8, where ankyrin gene is located
• 75-80% of patients with autosomal dominant HS
have combined spectrin and ankyrin deficiency
24. Cont…
Clinical features
• Signs of anemia
• Jaundice
• Splenomegally
Diagnosis
• Family hx
• Peripheral blood smear;
Spherocytes and reticulocytes
• FBC; - Mild to moderate
anemia
-Reticulocytosis
-Increased mean
corpuscular hemoglobin
concentration (MCHC)
• Hyperbilirubinemia
25. Management
• Splenectomy is the standard treatment for
patients with clinically severe HS
• Improves RBCs survival
26. Achondroplasia
• Is an AD genetic disorder caused by mutations
in the gene encoding the fibroblast growth
factor receptor 3 (FGFR3), making the
resulting protein overactive
• FGFR3 is a negative regulator of bone growth
• Achondroplasia is the most common form of
short-limb dwarfism and is characterized by
disproportionate shortness of limbs and
relative macrocephaly
27. Cont…
• 97% of achondroplasia is caused by a single point
mutation in the gene encoding FGFR3, in which a
glycine is substituted with an arginine residue at
position 380 of the FGFR3 a.a sequence
• Upon ligand binding, the mutation decreases the
elimination of the receptor/ligand complex
resulting in prolonged intracellular signaling
• Over-activity of FGFR3 inhibits chondrocyte
proliferation and restricts long bone length
28. Cont…
• Failure of a echondrial bone ossification (long
bones)
• Intramembranous ossification; normal
• Thus, achondroplastic dwarfs with normal
trunk size, but small arms and legs
• Macrocephaly with prominent forehead and
flattened nasal bridge
• Kyphosis
29. Management
• Currently no prevention or treatment
• Somatotropin (recombinant human growth
hormone); augment height, but does not
substantially affect the height of an individual
with achondroplasia
31. THE EXTRACELLULAR MATRIX
• Most mammalian cells are located in tissues
where they are surrounded by a complex
extracellular matrix (ECM) often referred to as
“connective tissue”
• The ECM contains three major classes of
biomolecules:
32. Cont…
1)The structural proteins;
a) Collagen; major component, 25% of proteins.
All collagen types have a triple helical structure.
Provides an extracellular framework. At least 28
distinct types of collagen made up of 30 distinct
polypeptide chains (each encoded by a separate
gene) have been identified in human tissues
Collagen form long rodlike fibers assembled by
lateral association of these triple helical units into
fibrils
34. Cont…
• Collagen biosynthesis is complex, involving at
least eight enzyme-catalyzed posttranslational
steps
• b)Elastin; a major protein component of
tissues that require elasticity such as arteries,
lungs, bladder, skin and elastic ligaments and
cartilage. Allows tissues in the body to resume
their shape after stretching or contracting
35. Cont…
c) Fibrillin; large glycoprotein secreted by
fibroblast. Found commonly in zonular fibers of
the lens, periostium, arterial walls. Major
structural component of microfibrils (fine fiber-
like strands which provide a scaffold for the
deposition of elastin in the ECM)
Fibrillin 1; major component of microfibril
Fibrillin 2; have a role in early elastogenesis
Fibrillin 3; mainly located in the brain
Fibrillin 4; structure is similar to fibrillin 2
36. Cont…
2) Certain specialized proteins such as
fibronectin, and laminin (adhesive
glycoproteins to attach cells to matrix)
3) Proteoglycans (mucoproteins); protein-
polysaccharide complexes. Combine with
collagen to form cartilage
37. Cont…
• The ECM is involved in many normal and
pathologic processes eg, it plays important
roles in development, in inflammatory states,
and in the spread of cancer cells
• Several diseases (eg, osteogenesis imperfecta
and a number of types of the Ehlers-Danlos
syndrome) are due to genetic disturbances of
the synthesis of collagen
38. Ehlers-Danlos syndrome
• Comprises a group of inherited disorders
whose principal clinical features are
i. Hyper-extensibility of the skin
ii. Abnormal tissue fragility
iii. Increased joint mobility
• The clinical picture is variable, reflecting
underlying extensive genetic heterogeneity
39. Cont…
• At least 10 types have been recognized, most but
not all of which reflect a variety of lesions in the
synthesis of collagen
• Type I; Classic EDS (COL5A1/2 gene mutation)
• Type IV is the most serious because of its
tendency for spontaneous rupture of arteries or
the bowel, reflecting abnormalities in type III
collagen (mutations in the COL3A1 gene)
• Patients with type VI, due to a deficiency of lysyl
hydroxylase, exhibit marked joint hypermobility
and a tendency to ocular rupture
42. Management;
• No cure
• Physical therapy; to strengthen the muscles
and stabilize joints
• Braces to prevent joint dislocation
43. Osteogenesis imperfecta
• Brittle-bone disease/ Blue-sclera syndrome
• Incidence 1:20,000
• A hereditary disease (AD) caused in 80% of cases
by a mutation of 1 or 2 genes (COL1A1 gene on
chromosome 17 encodes the pro-alpha1 chain,
and COL1A2 gene on chromosome 2 encodes the
pro-alpha2chain)
• Pathologic changes are seen in all tissues of
which type 1 collagen is an important constituent
(eg, bone, ligament, dentin, and sclera)
44. Cont…
• In OI due to quantitative defects of type 1
collagen, the mutations result in the production
of a premature stop codon or a microsense frame
shift, which leads to production of reduced
amounts of structurally normal collagen
• Qualitative defects, substitution of a larger amino
acid (eg, cysteine or alanine) for glycine results in
abnormal helix formation, but these chains can
combine with normal chains to produce type 1
collagen which is functionally impaired because
of the mutant chain
48. Management
• No cure
• Supportive; surgery if it is likely to improve
function eg; intramedullary rod placement,
correction of scoliosis
• Orthotics
• Bisphosphonates (eg, pamidronate) inhibit
osteoclast-mediated bone resorption on the
endosteal surface of bone. As a result unopposed
osteoblastic new bone formation on the
periosteal surface, increase in cortical thickness
49. Marfan syndrome
• Disorder caused by mutations in the FBN1
gene that encodes fibrillin, a glycoprotein of
the fibrous connective tissue
• Inherited as an AD trait; incidence 1:98,000
• Most cases are caused by missense mutations
in the gene (on chromosome 15) for fibrillin 1
• Fibrillin is found in the zonular fibers of the
lens, in the periosteum, and associated with
elastin fibers in the aorta (and elsewhere)
51. Clinical features
• It affects the eyes eg, causing dislocation of the
lens (ectopia lentis), cataracts, retinal
detachment
• The skeletal system; most patients are tall and
exhibit long digits (arachnodactyly),
thoracolumbar scoliosis, pectus deformities, and
hyperextensibility of the joints
• The cardiovascular system (eg, causing weakness
of the aortic media, leading to aortic dilatation
and dissection)
55. Management
• B-blockers reduces rate of aortic dilatation
• CCB??? As prophylaxis against aortic aneurism
progression (limited evidence)
• Surgical interventions (Prophylactic aortic root
surgery)
• Life expectancy depends on severity of
cardiovascular involvement
56. Scurvy
• Scurvy affects the structure of collagen. However,
it is due to a deficiency of ascorbic acid (vitamin
C) and is not a genetic disease
• Its major signs are bleeding gums, subcutaneous
hemorrhages, and poor wound healing
• These signs reflect defective synthesis of collagen
due to reduced activity of the enzymes prolyl and
lysyl hydroxylases, both of which require
ascorbic acid as a cofactor and are involved in
posttranslational modifications which give
collagen molecules rigidity
57. Other diseases of ECM
• Epidemolysis bullos(mutation in keratin gene)
• Cutis laxas (elastolysis)
• Alport syndrome
• Williams syndrome