Download Plasma Membrane Transporter Protein Mutations

Plasma Membrane Transporter Protein Mutations
Many disorders are produced by mutant proteins that impair the transport of nutrients into cells ( Table
216-3 ). Familial glucose-galactose malabsorption syndrome exemplifies defective transporter protein
and results in the accumulation of nontransported glucose in the intestinal lumen and refractory diarrhea
secondary to its osmotic effects. Direct evidence for genetic control of intestinal glucose transport in
humans was obtained by in vitro studies of jejunal biopsy material from families in which the affected
members expressed refractory diarrhea on ingesting d-galactose or d-glucose but not fructose.
Pedigree analysis conformed to autosomal recessive inheritance. These data predicted a gene that
coded for a stereospecific, sodium-dependent, and energy-dependent transporter protein in human
jejunal (and proximal renal tubular) microvilli. Expression cloning of active glucose transport has now
confirmed the presence of a family of glucose transporter genes, their deduced amino acid sequences,
and specific codon changes producing the syndromes of familial glucose-galactose malabsorption and
renal glycosuria.
TABLE 216-3
-- DISEASES CAUSED BY MUTATIONS IN PLASMA MEMBRANE TRANSPORT
PROTEINS
Tissue
Disease
B12 malabsorption
Affected
Ileum
Mode of
Substrate
Vitamin B12
Inheritance
Autosomal
Clinical Expression
Juvenile
recessive
Blue diaper
Gut
Tryptophan
syndrome
Primary carnitine
Kidney + gut
Carnitine
Gut
Chloride
chloridorrhea
Cystic fibrosis
Familial
Autosomal
Hypoglycemia,
recessive
hypotonia
Autosomal
Diarrhea, alkalosis
recessive
Apical
Chloride
Autosomal
Lung, intestinal
recessive
obstruction
Cystine + lysine,
Autosomal
Renal lithiasis
arginine, ornithine
recessive
(cystine)
Kidney + gut
Phosphate
X-linked dominant Rickets
Lymphocyte,
Methyltetrahydrofolate
Autosomal
epithelia
Cystinuria
Hypercalcemia
recessive
deficiency
Congenital
Autosomal
Kidney + gut
hypophosphatemic
rickets
Folate deficiency
erythrocyte
Glucose-galactose
malabsorption
Gut + kidney
Aplastic anemia
recessive
Glucose and galactose Autosomal
recessive
Refractory diarrhea
Tissue
Disease
Mode of
Affected
Hartnup's syndrome Gut + kidney
Substrate
Neutral amino acids
Inheritance
Clinical Expression
Autosomal
Nicotinic acid
recessive
deficiency
(pellagra)
Hereditary
Kidney
Phosphate
hypophosphatemic
Autosomal
Growth restriction,
dominant
rickets,
rickets
Hereditary renal
hypercalciuria
Kidney
Uric acid
hypouricemia
Hereditary
Erythrocyte
Sodium
spherocytosis
Hyperdibasic
Autosomal
Urolithiasis (uric
recessive
acid)
Autosomal
Hemolytic anemia
recessive
Kidney
aminoaciduria (type
Lysine, arginine,
Autosomal
?Symptoms
ornithine
dominant
Glycine, proline,
Autosomal
hydroxyproline
recessive
Lysine
Autosomal
Growth failure,
recessive
seizures
Autosomal
Growth restriction,
recessive
hyperammonemia,
I)
Iminoglycinuria
Isolated lysinuria
Kidney + gut
Kidney + gut
Lysinuric protein
Kidney,
intolerance (type II)
fibroblasts,
Lysine
hepatocytes,
Benign?
mental retardation
gut
Methionine
Gut
Methionine
malabsorption
Autosomal
Mental retardation,
recessive?
white hair, failure to
(oasthouse disease)
Renal glycosuria
thrive
Kidney
Glucose
Autosomal
Benign glycosuria
recessive
+
Renal tubular
Distal renal
H secretion, citrate,
Autosomal
Hypokalemia, growth
acidosis (type I)
tubule
calcium
dominant
restriction,
nephrocalcinosis
Renal tubular
Proximal
acidosis (type II)
renal tubule
Bicarbonate
“Familial”
Hyperchloremic
metabolic acidosis
Defects of Glucose Transporters
There are many inherited defects involving the plasma membrane transport of glucose that are caused by
mutations of either active or facilitative glucose transport. Glucose transporters are a family of proteins
whose definitions of function evolved after their cloning and molecular genetic analysis ( Table 216-4 ).
By comparing data from families with renal glycosuria and glucose-galactose malabsorption, it became
+
evident that different Na -dependent, active glucose transporters (sodium-glucose transporter [SGLT])
were present in kidney and gut epithelium. SGLT1 is shared by the kidney and gut, whereas SGLT2
functions predominantly in the kidney alone and causes renal glycosuria without glucose-galactose
malabsorption (see Table 216-4 ). An insulin-responsive, facilitative glucose transporter (GLUT4) is not
+
Na dependent and is expressed primarily in insulin-responsive tissues (fat cells, skeletal muscle). More
than one glucose transporter is expressed by most cells. The jejunal epithelial cell uses SGLT1 to
concentrate glucose from its luminal surface into the cytosol, then effluxes glucose at its basal-lateral
surfaces through GLUT2. GLUT2 is also involved in regulating the amount of glucose transported into
beta cells of the pancreas, a process that regulates glucose stimulation of insulin release. Indirect
evidence suggests that mutations in the GLUT2 gene are “sensitivity genes” involved in regulating insulin
secretion.
TABLE 216-4
-- HUMAN GLUCOSE TRANSPORTERS
mRNA
kD
Expression
Size
Chromosomal
in Tissue and
Protein (AA)
(kb)
Localization
Cells
Function
Disorder
GLUT1 55
2.8
lp35 ? p31.3
Blood-brain
Basal glucose
Seizures with low
barrier,
transport across most cerebrospinal fluid
erythrocyte,
cells, including the
and normal blood
fibroblast
blood-brain barrier
glucose
3q26.1 ? q26.3
Liver, kidney,
Low-affinity glucose
Defective insulin
beta cell of the
intestine,
diabetes
secretion in
Neurons,
Basal glucose
?
fibroblasts,
transport, high affinity
(492)
GLUT2 58
2.8
(524)
transport
3.4
pancreas
5.4
GLUT3 54
(496)
2.7
12p13.3
4.1
placenta,
testes
GLUT4 55
2.8
17p13 heart
Fat, skeletal
Insulin-stimulated
Defective
(509)
muscle,
transport, ?NIDDM
insulin-stimulated
3.5
glucose
Fructose transport
?
transport
GLUT5 50
2.0
1p32 ? p22
(501)
GLUT7 52
(rat)
(528)
Small
intestine
?
?
Liver
Glucose release from Type ID glycogen
microsome
disease
endoplasmic
reticulum
storage
mRNA
kD
Protein (AA)
Expression
Size
Chromosomal
in Tissue and
(kb)
Localization
Cells
Function
Disorder
Intestine,
Intestinal absorption,
Glucose-galactose
kidney
renal reabsorption,
malabsorption
(medulla)
high affinity (2 Na: 1
CONCENTRATIVE GLUCOSE TRANSPORTERS
SLGT1 75
2.2
22q11 ? qter
(664)
glucose)
2.6
4.8
SLGT2 76
2.4
16p11.2
(672)
3.0
Kidney
Low affinity, high
Renal glycosuria
(cortex)
capacity (1
Na: 1
3.5
glucose)
4.5
AA = amino acids; NIDDM = non–insulin-dependent diabetes mellitus.
(From:
http://www.mdconsult.com/das/book/body/105004881-4/748945761/1492/790.html#4-u1.0-B978-1-4160
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