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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

Disease

Tissue Affected

Substrate

Mode of Inheritance

Clinical Expression

B12 malabsorption

Ileum

Vitamin B12

Autosomal recessive

Juvenile

Blue diaper syndrome

Gut

Tryptophan

Autosomal recessive

Hypercalcemia

Primary carnitine deficiency

Kidney + gut

Carnitine

Autosomal recessive

Hypoglycemia, hypotonia

Congenital chloridorrhea

Gut

Chloride

Autosomal recessive

Diarrhea, alkalosis

Cystic fibrosis

Apical epithelia

Chloride

Autosomal recessive

Lung, intestinal obstruction

Cystinuria

Kidney + gut

Cystine + lysine, arginine, ornithine

Autosomal recessive

Renal lithiasis (cystine)

Familial hypophosphatemic rickets

Kidney + gut

Phosphate

X-linked dominant

Rickets

Folate deficiency

Lymphocyte, erythrocyte

Methyltetrahydrofolate

Autosomal recessive

Aplastic anemia

Glucose-galactose malabsorption

Gut + kidney

Glucose and galactose

Autosomal recessive

Refractory diarrhea

Hartnup's syndrome

Gut + kidney

Neutral amino acids

Autosomal recessive (pellagra)

Nicotinic acid deficiency

Hereditary hypophosphatemic rickets

Kidney

Phosphate

Autosomal dominant

Growth restriction, rickets, hypercalciuria

Hereditary renal hypouricemia

Kidney

Uric acid

Autosomal recessive

Urolithiasis (uric acid)

Hereditary spherocytosis

Erythrocyte

Sodium

Autosomal recessive

Hemolytic anemia

Hyperdibasic aminoaciduria (type I)

Kidney

Lysine, arginine, ornithine

Autosomal dominant

?Symptoms

Iminoglycinuria

Kidney + gut

Glycine, proline, hydroxyproline

Autosomal recessive

Benign?

Isolated lysinuria

Kidney + gut

Lysine

Autosomal recessive

Growth failure, seizures

Lysinuric protein intolerance (type II)

Kidney, fibroblasts, hepatocytes, gut

Lysine

Autosomal recessive

Growth restriction, hyperammonemia, mental retardation

Methionine malabsorption (oasthouse disease)

Gut

Methionine

Autosomal recessive?

Mental retardation, white hair, failure to thrive

Renal glycosuria

Kidney

Glucose

Autosomal recessive

Benign glycosuria

Renal tubular acidosis (type I)

Distal renal tubule

H+ secretion, citrate, calcium

Autosomal dominant nephrocalcinosis

Hypokalemia, growth restriction,

Renal tubular acidosis (type II)

Proximal 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

Protein

kD (AA)

mRNA Size (kb)

Chromosomal Localization

Expression in Tissue and Cells

Function

Disorder

GLUT1

55 (492)

2.8

lp35 ? p31.3

Blood-brain barrier, erythrocyte, fibroblast

Basal glucose transport across most cells, including the blood-brain barrier

Seizures with low cerebrospinal fluid and normal blood glucose

GLUT2

58 (524)

2.8

3q26.1 ? q26.3 beta cell of the transport pancreas

Liver, kidney, intestine,

Low-affinity glucose diabetes

Defective insulin secretion in

3.4

5.4

GLUT3

54 (496)

2.7

12p13.3

Neurons, fibroblasts, placenta, testes

Basal glucose transport, high affinity

?

4.1

GLUT4

55 (509) 3.5

2.8

17p13 heart

Fat, skeletal muscle, glucose transport

Insulin-stimulated transport, ?NIDDM

Defective insulin-stimulated

GLUT5

50 (501)

2.0

1p32 ? p22

Small intestine

Fructose transport

?

GLUT7 (rat)

52 (528)

?

?

Liver microsome endoplasmic reticulum

Glucose release from disease

Type ID glycogen storage

CONCENTRATIVE GLUCOSE TRANSPORTERS

SLGT1

75 (664)

2.2

22q11 ? qter

Intestine, kidney (medulla)

Intestinal absorption, renal reabsorption, high affinity (2 Na: 1 glucose)

Glucose-galactose malabsorption

 

2.6

 

 

 

 

 

4.8

 

 

 

 

SLGT2

76 (672)

2.4

16p11.2

Kidney (cortex) capacity (1 Na: 1 glucose)

Low affinity, high

Renal glycosuria

3.0

3.5

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-B978-1-4160-2805-5..50221-4--cesec24_9675)

 



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