Chapter 190

## Abstract

Abstract

1. Glucose-galactose malabsorption (GGM, MIM 182380) is a rare autosomal recessive disorder that is due to mutations in the gene coding for the intestinal brush-border sodium-glucose cotransporter (SGLT1). It is characterized by the neonatal onset of profuse, watery diarrhea that leads to severe dehydration and death if left untreated. The intestinal absorption of other nutrients such as amino acids and fructose is normal. Frequently, GGM is accompanied by a mild renal glucosuria. The diarrhea is quickly resolved by the elimination of glucose, galactose, and lactose from the diet; the milk sugar lactose is quickly hydrolyzed to glucose and galactose by lactase on the surface of the intestinal mucosa. The malabsorption of glucose and galactose is readily confirmed by the breath hydrogen test. Once the offending sugars are removed from the diet, patients appear to grow and develop normally.

2. SGLT1 is present in the brush-border membrane of mature enterocytes lining the upper surface of the intestinal villi. The transporter is responsible for the accumulation of glucose and galactose in the enterocytes, and this occurs by sodium-sugar cotransport. Two sodium ions are transported along with each sugar, and transport is energized by the sodium electrochemical potential gradient across the brush-border membrane. The sodium gradient is maintained by the Na+/K+ pump in the basolateral membrane of the enterocyte. This means that sugar in the gut lumen stimulates sodium absorption across the small intestine, and this is followed by anions and water. This process provides the rationalization for oral rehydration therapy used worldwide to treat diarrhea caused by infections. Fructose is not transported by SGLT1, but it uses its own facilitated transporter in the brush-border membrane, GLUT5. Once glucose, galactose, and fructose are within the cell, they exit to the blood across the basolateral membrane of the cell through another facilitated sugar transporter, GLUT2.

3. In 46 GGM patients, the SGLT1 gene has been screened for mutations, and 41 have been identified. These include missense (61 percent), nonsense (10 percent), frameshift (17 percent), and splice-site (12 percent) mutations. About 70 percent have homozygous mutations, whereas the remainder bear compound heterozygous mutations. No mutations have yet been identified in 3 GGM patients. The missense and several of the nonsense mutations have been tested for defects in sugar transport. The mutant proteins were expressed in a heterologous expression system, Xenopus laevis oocytes, and all but 3 missense mutations cause a severe reduction in sodium-sugar transport activity. In 2 of the 3 patients with these rather benign mutations, other mutations impaired sugar transport.

4. The nonsense, frameshift, and splice-site mutations produce inactive proteins. The missense mutant cRNAs are translated and glycosylated in the oocyte endoplasmic reticulum and remain in the cell at about the same level as the wild-type protein. The majority are retained in the endoplasmic reticulum or Golgi apparatus and are not forwarded to the plasma membrane of the oocyte. This indicates that the mutations cause protein misfolding that impairs proper trafficking to the plasma membrane. Only one missense mutant, Q457R, is properly processed in oocytes, but this mutant protein is unable to transport sugar. Immunocytochemical examination of the mucosal biopsies from four GGM patients confirms the conclusions drawn about mutant protein trafficking in the expression system. Thus GGM joins a growing list of disorders in which mutations cause protein folding and trafficking defects.

5. Hereditary renal glycosuria (MIM *8233100) is an autosomal recessive disease that results from the selective inability of the kidney to reabsorb glucose from the glomerular filtrate in the absence of hyperglycemia. The amount of glucose excreted is independent of diet, and oral tolerance tests and plasma insulin levels are normal. These patients only excrete glucose, not galactose, and they store and use carbohydrate normally. Patients with hereditary renal glycosuria do not have a defect in intestinal glucose absorption, and those with GGM do not show a severe renal glycosuria. These characteristics indicate that hereditary renal glycosuria is due to a defect in another sodium-glucose cotransporter in the brush border of the early proximal tubule, i.e., SGLT2. There is some uncertainty about the identity of the human renal SGLT2.

Sign in to your MyAccess profile while you are actively authenticated on this site via your institution (you will be able to verify this by looking at the top right corner of the screen - if you see your institution's name, you are authenticated). Once logged in to your MyAccess profile, you will be able to access your institution's subscription for 90 days from any location. You must be logged in while authenticated at least once every 90 days to maintain this remote access.

Ok

## Subscription Options

### OMMBID Full Site: One-Year Subscription

Connect to the full suite of OMMBID content including new and revised chapters that reflect the latest research, image galleries, clinical phenotypes, and more.