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Specific membrane transporters mediate the passage of a wide variety of substances across cellular membranes. Classes of substrates include amino acids, sugars, cations, anions, vitamins, and water. The number of inherited disorders of membrane transport continues to increase with the identification of new transporters on the plasma membrane or intracellular organelles and the clarification of the molecular basis of diseases with previously unknown pathophysiology. The first transport disorders identified affected the gut or the kidney, but transport processes are now proving essential for the normal function of every organ. Mutations in transporter molecules cause disorders of the heart, muscle, brain, and endocrine and sensory organs (Table 435e-1). Inherited defects impairing the transport of selected amino acids that can present in adults are discussed here as examples of the abnormalities encountered; others are considered elsewhere in this text.


Cystinuria (frequency of 1 in 10,000 to 1 in 15,000) is an autosomal recessive disorder caused by defective transporters in the apical brush border of proximal renal tubule and small intestinal cells. It is characterized by impaired reabsorption and excessive urinary excretion of the dibasic amino acids lysine, arginine, ornithine, and cystine. Because cystine is poorly soluble, its excess excretion predisposes to the formation of renal, ureteral, and bladder stones. Such stones are responsible for the signs and symptoms of the disorder.

There are two variants of cystinuria. Homozygotes for both variants have high urinary excretion of cystine, lysine, arginine, and ornithine. Type I heterozygotes usually have normal urinary amino acid excretion, whereas most non–type I (formerly type II and type III) heterozygotes have moderately increased urinary excretion of each of the four amino acids. The gene for type I cystinuria (SLC3A1, chromosome 2p16.3) encodes a membrane glycoprotein. Non–type I cystinuria is caused by mutations in SLC7A9 (chromosome 19q13) that encodes the b0,+ amino acid transporter. The glycoprotein encoded by SLC3A1 favors the correct processing of the b0,+ membrane transporter and explains why mutations in two different genes cause a similar disease.

Cystine stones account for 1–2% of all urinary tract calculi but are the most common cause of stones in children. Cystinuria homozygotes regularly excrete 2400–7200 μmol (600–1800 mg) of cystine daily. Since the maximum solubility of cystine in the physiologic urinary pH range of 4.5–7.0 is about 1200 μmol/L (300 mg/L), cystine needs to be diluted to 2.5–7 L of water to prevent crystalluria. Stone formation usually manifests in the second or third decade but may occur in the first year of life. Symptoms and signs are those typical of urolithiasis: hematuria, flank pain, renal colic, obstructive uropathy, and infection (Chap. 342). Recurrent urolithiasis may lead to progressive renal insufficiency.

Cystinuria is suspected after observing typical hexagonal crystals in the sediment of acidified, concentrated, chilled urine or after performing a urinary nitroprusside test. Quantitative ...

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