Molecular Basis of Diseases
Molecular Genetics
Immunology
Metabolic Disorders
Gert-Jan Wiggers
,Molecular Genetics
,LE 1 Introduction Human Genetics 31-01-2022
Cystic fibrosis
- Most common monogenic disorder
that we have
- Monogenic = one change, one
mutation, that is most common
- Pancreas important organ for
symptoms: blocked pancreatic duct.
Pancreas can’t get its stuff from ducts
to intestine.
- Pancreatic duct: supplies bile (gal) to
acid digestion.
Lung:
Step 1. Chloride secretion in a pulmonary secretory
epithelial cell. The ability of secretory epithelia to secret
fluid rests on the energy provided by the ubiquitous
(found everywhere), basolaterally (situated to the
base/side) located Na+/K+-ATPase, which maintains a
low intracellular concentration of Na+ by actively
pumping it out of the cell. The low intracellular Na+
concentration, coupled with the high extracellular Na+
concentration and the negative transmembrane
potential, drives the passive diffusion of Na+ into the cell
down the concentration gradient.
Step 2. The channel through which this passive diffusion
occurs (the Na+/K+/2Cl- cotransporter) requires
concomitant (naturally accompanying or associated)
transport of Na+, K+, and Cl- for any transport to occur at
all. Thus, the passive diffusion of Na+ into the cell is
coupled with an intracellular accumulation of Cl- against its electrochemical gradient.
Step 3. When the cell is stimulated to secrete, Cl- channels open, allowing Cl- to exit down its
electrochemical gradient. Cystic fibrosis transmembrane regulator (CFTR).
Step 4. Sodium ions follow the Cl- ions through a paracellular pathway (transfer of substances across
an epithelium by passing through the intercellular space between the cells), and water follows the salt
due to the resulting osmotic gradient. Extrusion error.
Low chloride concentration in lungs.
, Skin:
Diagram of a sweat gland,
showing paths taken by
chloride ions (arrows)
during secretion. In both
normal and CF sweat
glands in the dermis,
chloride is present in
secretions at a
concentration of 105 mEq,
equalling that in serum
(‘’isotonic’’).
(Top) In the normal sweat
gland, chloride is absorbed
out of the sweat in a CFTR-
dependent manner as the sweat travels from the glad to the skin surface. As a result, the chloride
concentration in normal sweat is below that in serum (‘’hypotonic’’), with <40 mEq considered normal
and <20 mEq being typical
(Bottom) In the CF sweat gland, chloride absorption is hindered by defective CFTR function. As a result,
sweat which reaches the skin surface has higher than normal chloride concentrations (>60 mEq).
Resorption mistake.
Sweat test:
• High tripsin levels.
• Electrode drives the medicine into the skin, causing sweat-
reaction.
• Sweat is collected on filter paper.
• Conductance of the sweat is measured.
• Cystic fibrosis: higher chloride concentration is sweat.
Resorption mistake
What is the main difference in Cl- transport between lungs and a
sweat gland?
Extrusion error in lungs and resorption error in skin.
Molecular Genetics
Immunology
Metabolic Disorders
Gert-Jan Wiggers
,Molecular Genetics
,LE 1 Introduction Human Genetics 31-01-2022
Cystic fibrosis
- Most common monogenic disorder
that we have
- Monogenic = one change, one
mutation, that is most common
- Pancreas important organ for
symptoms: blocked pancreatic duct.
Pancreas can’t get its stuff from ducts
to intestine.
- Pancreatic duct: supplies bile (gal) to
acid digestion.
Lung:
Step 1. Chloride secretion in a pulmonary secretory
epithelial cell. The ability of secretory epithelia to secret
fluid rests on the energy provided by the ubiquitous
(found everywhere), basolaterally (situated to the
base/side) located Na+/K+-ATPase, which maintains a
low intracellular concentration of Na+ by actively
pumping it out of the cell. The low intracellular Na+
concentration, coupled with the high extracellular Na+
concentration and the negative transmembrane
potential, drives the passive diffusion of Na+ into the cell
down the concentration gradient.
Step 2. The channel through which this passive diffusion
occurs (the Na+/K+/2Cl- cotransporter) requires
concomitant (naturally accompanying or associated)
transport of Na+, K+, and Cl- for any transport to occur at
all. Thus, the passive diffusion of Na+ into the cell is
coupled with an intracellular accumulation of Cl- against its electrochemical gradient.
Step 3. When the cell is stimulated to secrete, Cl- channels open, allowing Cl- to exit down its
electrochemical gradient. Cystic fibrosis transmembrane regulator (CFTR).
Step 4. Sodium ions follow the Cl- ions through a paracellular pathway (transfer of substances across
an epithelium by passing through the intercellular space between the cells), and water follows the salt
due to the resulting osmotic gradient. Extrusion error.
Low chloride concentration in lungs.
, Skin:
Diagram of a sweat gland,
showing paths taken by
chloride ions (arrows)
during secretion. In both
normal and CF sweat
glands in the dermis,
chloride is present in
secretions at a
concentration of 105 mEq,
equalling that in serum
(‘’isotonic’’).
(Top) In the normal sweat
gland, chloride is absorbed
out of the sweat in a CFTR-
dependent manner as the sweat travels from the glad to the skin surface. As a result, the chloride
concentration in normal sweat is below that in serum (‘’hypotonic’’), with <40 mEq considered normal
and <20 mEq being typical
(Bottom) In the CF sweat gland, chloride absorption is hindered by defective CFTR function. As a result,
sweat which reaches the skin surface has higher than normal chloride concentrations (>60 mEq).
Resorption mistake.
Sweat test:
• High tripsin levels.
• Electrode drives the medicine into the skin, causing sweat-
reaction.
• Sweat is collected on filter paper.
• Conductance of the sweat is measured.
• Cystic fibrosis: higher chloride concentration is sweat.
Resorption mistake
What is the main difference in Cl- transport between lungs and a
sweat gland?
Extrusion error in lungs and resorption error in skin.
