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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 -2805-5..50221-4--cesec24_9675)