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Mendelian Phenotypes as “Probes” of Renal Transport Systems for Amino Acids and Phosphate

Charles R. Scriver, Harriet S. Tenenhouse

10.1002/cphy.cp080242

Source: Supplement 25: Handbook of Physiology, Renal Physiology

Originally published: 1992

Published online: January 2011

Full Article on Wiley Online Library



Abstract

The sections in this article are:

1 Genetic Considerations
1.1 Chemical Phenotypes
1.2 Polypeptide Phenotypes
1.3 Genotypes
2 Homeostasis: The Concept of Heritability
3 Physiological Considerations of Renal Transport
3.1 Radial Specificity
3.2 Axial Specificity
3.3 Chemical Specificity
4 Mendelian Phenotypes
4.1 Disorders of Cationic Amino Acid Transport
4.2 Disorders of Neutral Amino Acid Transport
4.3 Disorders of Anionic (Acidic) Amino Acid Transport
4.4 Disorders of Phosphate Transport
4.5 Fanconi Syndrome and Allied Disorders
5 Resumé of Findings in Mendelian Renal Transport Phenotypes and Their Implications
5.1 Taxonomy
5.2 Heterogeneity of Carriers
5.3 Homeostasis
6 Cell Biology and Molecular Genetics
Figure 1. Figure 1.

Top: model of renal reabsorption process (flux J1, J2) drawn to accommodate disorders affecting net reabsorption of metabolic substrates (S) such as amino acids and phosphate. Reabsorption begins at luminal membrane (flux J3) with substrate and Na+ moving from lumen to cell by coupled cotransport on symport. Influx of S can be against electrochemical gradient, while movement of Na+ is down its gradient. Steady state of S in open system (in vivo and in situ) is not necessarily equivalent to chemical equilibrium condition in corresponding closed system (in vitro) because of substrate “runout” into alternative chemical (metabolic) pools (flux B, J7) by backflux (J4) and paracellular leak (P) and transport (facilitated diffusion) by basolateral carriers to peritubular space (flux A, J5). Mediated uptake (flux J6) of S, for nutrient purposes, occurs at basolateral membrane (BLM) on carriers with chemical specificity. Whether efflux (J5, for reabsorptive process) and uptake (J6, for nutrition) of S occur on same or on different carriers is moot. Basolateral Na+,K+ ‐ATPase, required for primary active transport to maintain associated secondary active transport of S at brush border membrane (BBM), is implied but not shown. SL, luminal substrate; Sc, cellular substrate; SE, extracellular fluid substrate. Bottom: mendelian disorders that impair net reabsorption can affect , carriers for S at luminal membrane (by altering their number of carriers, their coupling to the Na+ gradient, or their affinity for S on either luminal or cytoplasmic surface) and either influx (decreased) as in or efflux (increased) as in ; , metabolic runout; and , mediated efflux at basolateral membrane. Open triangles, luminal origin of metabolite; closed triangles, cellular source of metabolite; open circles, conversion products of luminal metabolite; closed rectangles, impaired function; dashed arrows, deviant pathways.

From Bergeron and Scriver 27
Figure 2. Figure 2.

Effect of mutant allele (heterzygous genotype) on phenotype value (shown as net flux value, ordinate) when allele alters quantitative activity of one catalyst (shown as relative activity value, abscissa) in homeostatic system with one component or more (e.g., two, three, or nine components). Relation between variant genotype and flux value is linear in one‐component system and nonlinear in multiple‐component systems.

Adapted from Kacser and Burns 145
Figure 3. Figure 3.

Distribution of quantitative (phenotype) values in homeostatic system. A: normal distribution, with central tendency (mean value, x) and dispersion between outlier values (0 to 1). Central tendency is maintained by coherent behavior conferred by genotype (G). Dispersion is increased by experience (E) overriding the homeostatic system. B: deviant values, with mean distributions x' and x” in quasicontinuous and discontinuous variant phenotypes, respectively (see text for discussion).
Figure 4. Figure 4.

Top: relationship between fractional reabsorption (FR) of α‐aminoisobutyrate (AIB) and plasma AIB concentration in nine individual rats under uniform conditions of AIB infusion; plasma AIB is directly proportional to FRAIB. Open squares, low infusion rate; open circles, high infusion rate. Bottom: interindividual variation in fractional excretion (FE) of AIB is greater by ∼30‐fold than intraindividual variation (∼10%) in rats at steady state infused with AIB under uniform conditions. Evidence for heritability of FRAIB in rat.
Figure 5. Figure 5.

Topological heterogeneity in reabsorption processes shared by particular substrates in proximal nephron. Segments (S) SA and SB contain systems A and B, which have different properties (axial heterogeneity), A and A' and B and B' being different mediations of transmembrane transport (radial heterogeneity). Model is based on evidence from mendelian phenotypes and physiological studies.
Figure 6. Figure 6.

Plasma amino acid values in Hartnup patients and control siblings. Summed values are shown for 11 amino acids affected in Hartnup phenotype (A) and for remaining amino acids not thus affected (B). ○, Hartnup subjects; •, nonaffected controls. Lines crossing between columns indicate affected and nonaffected siblings; vertical lines within columns indicate siblings of like genotype. Mean values and distributions are not different in Hartnup and control groups. Two symptomatic Hartnup probands () are low outliers in A and B; their unaffected siblings are also low outliers in control group (A). Evidence that background genotype determines threshold for symptomatic expression of Hartnup mutation.

From Scriver et al. 276.
Figure 7. Figure 7.

Left: distribution of serum phosphorus values as inorganic phosphate in children and adolescents (6–17 yr). Right: association between age‐dependent mean serum phosphate values in male and female youths and adults and renal reabsorption expressed as Tmp/GFR.

Drawn from primary data on serum phosphate values and other data supplied by Kruse et al. 162


Figure 1.

Top: model of renal reabsorption process (flux J1, J2) drawn to accommodate disorders affecting net reabsorption of metabolic substrates (S) such as amino acids and phosphate. Reabsorption begins at luminal membrane (flux J3) with substrate and Na+ moving from lumen to cell by coupled cotransport on symport. Influx of S can be against electrochemical gradient, while movement of Na+ is down its gradient. Steady state of S in open system (in vivo and in situ) is not necessarily equivalent to chemical equilibrium condition in corresponding closed system (in vitro) because of substrate “runout” into alternative chemical (metabolic) pools (flux B, J7) by backflux (J4) and paracellular leak (P) and transport (facilitated diffusion) by basolateral carriers to peritubular space (flux A, J5). Mediated uptake (flux J6) of S, for nutrient purposes, occurs at basolateral membrane (BLM) on carriers with chemical specificity. Whether efflux (J5, for reabsorptive process) and uptake (J6, for nutrition) of S occur on same or on different carriers is moot. Basolateral Na+,K+ ‐ATPase, required for primary active transport to maintain associated secondary active transport of S at brush border membrane (BBM), is implied but not shown. SL, luminal substrate; Sc, cellular substrate; SE, extracellular fluid substrate. Bottom: mendelian disorders that impair net reabsorption can affect , carriers for S at luminal membrane (by altering their number of carriers, their coupling to the Na+ gradient, or their affinity for S on either luminal or cytoplasmic surface) and either influx (decreased) as in or efflux (increased) as in ; , metabolic runout; and , mediated efflux at basolateral membrane. Open triangles, luminal origin of metabolite; closed triangles, cellular source of metabolite; open circles, conversion products of luminal metabolite; closed rectangles, impaired function; dashed arrows, deviant pathways.

From Bergeron and Scriver 27


Figure 2.

Effect of mutant allele (heterzygous genotype) on phenotype value (shown as net flux value, ordinate) when allele alters quantitative activity of one catalyst (shown as relative activity value, abscissa) in homeostatic system with one component or more (e.g., two, three, or nine components). Relation between variant genotype and flux value is linear in one‐component system and nonlinear in multiple‐component systems.

Adapted from Kacser and Burns 145


Figure 3.

Distribution of quantitative (phenotype) values in homeostatic system. A: normal distribution, with central tendency (mean value, x) and dispersion between outlier values (0 to 1). Central tendency is maintained by coherent behavior conferred by genotype (G). Dispersion is increased by experience (E) overriding the homeostatic system. B: deviant values, with mean distributions x' and x” in quasicontinuous and discontinuous variant phenotypes, respectively (see text for discussion).



Figure 4.

Top: relationship between fractional reabsorption (FR) of α‐aminoisobutyrate (AIB) and plasma AIB concentration in nine individual rats under uniform conditions of AIB infusion; plasma AIB is directly proportional to FRAIB. Open squares, low infusion rate; open circles, high infusion rate. Bottom: interindividual variation in fractional excretion (FE) of AIB is greater by ∼30‐fold than intraindividual variation (∼10%) in rats at steady state infused with AIB under uniform conditions. Evidence for heritability of FRAIB in rat.



Figure 5.

Topological heterogeneity in reabsorption processes shared by particular substrates in proximal nephron. Segments (S) SA and SB contain systems A and B, which have different properties (axial heterogeneity), A and A' and B and B' being different mediations of transmembrane transport (radial heterogeneity). Model is based on evidence from mendelian phenotypes and physiological studies.



Figure 6.

Plasma amino acid values in Hartnup patients and control siblings. Summed values are shown for 11 amino acids affected in Hartnup phenotype (A) and for remaining amino acids not thus affected (B). ○, Hartnup subjects; •, nonaffected controls. Lines crossing between columns indicate affected and nonaffected siblings; vertical lines within columns indicate siblings of like genotype. Mean values and distributions are not different in Hartnup and control groups. Two symptomatic Hartnup probands () are low outliers in A and B; their unaffected siblings are also low outliers in control group (A). Evidence that background genotype determines threshold for symptomatic expression of Hartnup mutation.

From Scriver et al. 276.


Figure 7.

Left: distribution of serum phosphorus values as inorganic phosphate in children and adolescents (6–17 yr). Right: association between age‐dependent mean serum phosphate values in male and female youths and adults and renal reabsorption expressed as Tmp/GFR.

Drawn from primary data on serum phosphate values and other data supplied by Kruse et al. 162
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Article Title: Mendelian Phenotypes as “Probes” of Renal Transport Systems for Amino Acids and Phosphate
 

How to Cite

Charles R. Scriver, Harriet S. Tenenhouse. Mendelian Phenotypes as “Probes” of Renal Transport Systems for Amino Acids and Phosphate. Compr Physiol 2011, Supplement 25: Handbook of Physiology, Renal Physiology: 1977-2016. First published in print 1992. doi: 10.1002/cphy.cp080242