Congenital Lactase Deficiency: Mutations, Functional and Biochemical Implications, and Future Perspectives.

Congenital lactase deficiency (CLD) is a severe autosomal recessive genetic disorder that affects the functional capacity of the intestinal protein lactase-phlorizin hydrolase (LPH). This disorder is diagnosed already during the first few days of the newborn's life due to the inability to digest lactose, the main carbohydrate in mammalian milk. The symptoms are similar to those in other carbohydrate malabsorption disorders, such as congenital sucrase-isomaltase deficiency, and include severe osmotic watery diarrhea. CLD is associated with mutations in the translated region of the LPH gene that elicit loss-of-function of LPH. The mutations occur in a homozygote or compound heterozygote pattern of inheritance and comprise missense mutations as well as mutations that lead to complete or partial truncations of crucial domains in LPH, such as those linked to the folding and transport-competence of LPH and to the catalytic domains. Nevertheless, the identification of the mutations in CLD is not paralleled by detailed genotype/protein phenotype analyses that would help unravel potential pathomechanisms underlying this severe disease. Here, we review the current knowledge of CLD mutations and discuss their potential impact on the structural and biosynthetic features of LPH. We also address the question of whether heterozygote carriers can be symptomatic for CLD and whether genetic testing is needed in view of the severity of the disease.

Frequency of lactose malabsorption among healthy southern and northern Indian populations by genetic analysis and lactose hydrogen breath and tolerance tests.

BACKGROUND: Lactose malabsorption (LM), the inability to break down lactose into glucose and galactose, is due to a deficiency in the small intestinal lactase phlorizin hydrolase enzyme. Ethnic and geographic variations of LM are known. OBJECTIVE: The aim of this study was to compare the frequency of LM in healthy southern and northern Indian populations. DESIGN: A total of 153 healthy volunteers (76 from southern and 77 from northern India) were evaluated for LM by using a lactose tolerance test (LTT), a lactose hydrogen breath test (lactose HBT), and polymerase chain reaction-restriction fragment length polymorphism to identify the lactase gene C/T-13910 polymorphism (confirmed by sequencing). RESULTS: Volunteers from southern and northern India were comparable in age and sex. The LTT result was abnormal in 88.2% of southern Indians and in 66.2% of northern Indians (P = 0.001). The lactose HBT result was abnormal in 78.9% of southern Indians and in 57.1% of northern Indians (P = 0.003). The CC genotype was present in 86.8% and 67.5% (P = 0.002), the CT genotype was present in 13.2% and 26.0% (P = 0.036), and the TT genotype was present in 0% and 6.5% (P = 0.03) of southern and northern Indians, respectively. The frequency of symptoms after the lactose load (47.4% compared with 15.6%; P < 0.001) and peak concentrations of breath hydrogen (88.5 +/- 71.9 compared with 55.4 +/- 61.9 ppm; P = 0.003), both of which might indicate the degree of lactase deficiency, were higher in southern than in northern Indians. CONCLUSION: The frequency and degree of LM is higher in southern than in northern Indian healthy populations because of genetic differences in these populations.

Molecular and cellular aspects and regulation of intestinal lactase-phlorizin hydrolase.

Carbohydrates are hydrolyzed in the intestinal lumen by specific enzymes to monosaccharides before transport across the brush border membrane of epithelial cells into the cell interior. The enzymes implicated in the digestion of carbohydrates in the intestinal lumen are membrane-bound glycoproteins that are expressed at the apical domain of the enterocytes. Absent or reduced activity of one of these enzymes is the cause of disaccharide intolerance and malabsorption, the symptoms of which are abdominal pain, cramps or distention, flatulence, nausea and osmotic diarrhea. Lactose intolerance is the most common intestinal disorder that is associated with an absence or drastically reduced levels of an intestinal enzyme, in this case lactase-phlorizin hydrolase (LPH). The pattern of reduction of activity has been termed late onset of lactase deficiency or adult type hypolactasia. It was thought that the regulation of LPH was post-translational and was associated with altered structural features of the enzyme. Recent studies, however, suggest that the major mechanism of regulation of LPH is transcriptional. Other forms of lactose intolerance include the rare congenital lactase deficiency and secondary forms, such as those caused by mucosal injury, due to infectious gastroenteritis, celiac disease, parasitic infection, drug-induced enteritis and Crohn's disease. This review will shed light on important strucural and biosynthetic aspects of LPH, the role played by particular regions of the LPH protein in its transport, polarized sorting, and function, as well as on the gene expession and regulation of the activity of the enzyme.

Human adult-onset lactase decline: an update.

Human adult-onset lactase decline is a biologic feature characteristic of the maturing intestine in the majority of the world's population. The digestion and absorption of lactose, the major carbohydrate in milk and also the main substrate for lactase, is often variable, a consequence of lactase levels, gastric emptying rate, and colonic salvage. Although commercially available "lactase" products alleviate symptoms in many lactose-intolerant people, a greater understanding of this variability in lactose tolerance could lead to interventions that reduce the rate of gastric emptying and/or increase the proliferation of lactose-metabolizing bacteria in the colon, leading to more efficient lactose utilization. Adult-onset lactase decline appears to be a risk factor for developing osteoporosis, owing to avoidance of dairy products or interference of undigested lactose with calcium absorption. Elderly with both adult-onset lactase decline and atrophic gastritis or those undergoing anti-ulcer treatment may have an increased risk of low calcium absorption owing to the lack of gastric acid that facilitates calcium uptake. Thus, lactose-intolerant elders should monitor their calcium nutrition status carefully.

Molecular aspects of disaccharidase deficiencies.

We have described the methods used for studying the biosynthesis and the post-translational processing of sucrase-isomaltase (SI), lactase-phlorizin hydrolase (LPH) and maltase-glucoamylase (MGA) in human small intestinal mucosa. Our results are discussed in the context of findings by other researchers. A surprising finding coming out of all these studies is that SI, LPH and MGA are structurally quite different. SI and LPH are both synthesized as large molecular weight precursors which are proteolytically processed to the mature enzymes. In the case of SI, this processing occurs after insertion of the precursor into the brush border membrane and is catalysed by pancreatic proteases; the mature form consists of the two subunits sucrase and isomaltase, the latter containing an N-terminal peptide anchor. Proteolytic processing of the LPH-precursor occurs intracellularly, yielding a mature enzyme in the form of a two active site polypeptide which is anchored via a C-terminal peptide. The role of the large cleaved propolypeptide of LPH is not yet known. MGA is the largest of the three disaccharidases, having a molecular weight of greater than 300 kDa. No proteolytic processing seems to be taking place during biogenesis of MGA in human mucosa, and the mode of attachment to the membrane is unknown at present. The application of the methods described to the investigation of congenital sucrase-isomaltase deficiency (CSID) and lactase restriction in adults is presented and differences between CSID and LPH restriction are discussed.