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Several polymorphic loci linked to lactase persistence (LP) have been described, all located in a small mutational hotspot region far upstream (∼14 kb) of the lactase (LCT) gene. One is typically found in Europeans,LCT–13910C > T, several others are found in East Africans and Arabs, e.g.LCT–13907C > G andLCT–13915T > G. The possibility of similar loci, specific to populations in South and Central America, has not received much attention so far. To identify possible novel polymorphisms in the mutational hotspot region, we sampled 158 subjects from a rural area in South-Central Mexico. DNA was isolated from serum, and Sanger sequencing of a 501 bp region spanning theLCT–13910C > T hotspot was successfully performed in 150 samples. The frequency of the European-typeLCT–13910 T-allele wasq = 0.202, and 35% of the population was thus lactase-persistent (CT or TT). Sixteen novel genetic variants were found amongst 11 of the subjects, all were heterozygotes: seven of the subjects were also carriers of at least oneLCT–13910 T-allele. Thus, the mutational hotspot region is also a hotspot in the rural Mexican population: 11/150 subjects carried a total of 16 previously unknown private mutations but no novel polymorphism was found. The relationship between such novel genetic variants in Mexicans and lactase persistence is worthy of more investigation. [ABSTRACT FROM PUBLISHER]

Background: Congenital lactase deficiency is an extremely rare gastrointestinal disorder characterized by neonatal-onset watery diarrhoea and failure to thrive. We present the first genetically confirmed case of congenital lactase deficiency in Central Europe. Case presentation: After an uneventful pregnancy and birth, a male newborn of consanguineous parents of Turkish origin presented with watery diarrhoea. On day 17, he was admitted to hospital with weight loss, hypertonic dehydration, and metabolic acidosis. Additionally, the patient showed an elevated calcium concentration in blood and urine as well as nephrocalcinosis. Diarrhoea stopped during intravenous rehydration and when feeding a glucose-, galactose-, and lactose-free formula. Therefore, glucose-galactose-malabsorption was assumed. However, genetic testing of the SGLT1 (SLC5A1) gene was negative and, indeed, feeding maltodextrine did not result in recurrence of diarrhoea. In contrast, lactose feeding immediately caused watery diarrhoea, suggesting congenital lactase deficiency. Genetic testing of the LCT gene revealed homozygosity for a 1-bp deletion in exon 8 (c.3448delT). Because of the nature of the mutation, causing a frame shift and a premature termination of translation, congenital lactase deficiency was confirmed and intestinal biopsies were unnecessary. The patient's general condition improved substantially on a lactose-free diet, including hypercalcaemia, hypercalciuria, and nephrocalcinosis which, however, only disappeared after months. Conclusion: This case demonstrates (a) that congenital lactase deficiency should be considered in cases of severe neonatal diarrhoea, (b) that intestinal biopsies can be avoided in typical cases that are confirmed by genetic testing, and (c) that the associated nephrocalcinosis can be reversed on diet and an appropriate fluid management. [ABSTRACT FROM AUTHOR]

Background: Lactase persistence is an inherited autosomal dominant trait that confers the ability to digest lactose after weaning. Lactose persistence is caused by single nucleotide variants in a regulatory element for the lactase gene (LCT). In Europeans, lactase persistence is associated with the nucleotide variant LCT -13910C>T. Ethnic groups from Africa and the Arabian Peninsula have other lactase persistence variants in close proximity to the -13910C>T variant. Current hybridisation probe analysis methods have been limited by the inability to detect all the known nucleotide variants. The aim of this study was to devise a method based on hybridisation probes and melting curve analysis for rapidly detecting LCT variants. Methods: We designed hybridisation probes for producing melting curve profiles that could identify seven LCT nucleotide variants: -13907C>G, -13910C>T, -13913T>C, -13914G>A, -13915T>G, -14009T>G, and -14010G>C. To validate the assay, we generated plasmid standards of all the alleles and mixed them to create artificial heterozygote samples. Results: All genotypes could be detected in a single tube assay. Rare genotypes were confirmed in a second assay with probes that had different complementary sequences. Conclusions: This assay can be used for rapidly genotyping lactase persistence in multi-ethnic populations. [ABSTRACT FROM AUTHOR]

Patients with the rare autosomal recessive disorder congenital lactase deficiency (CLD) present with severe, potentially life-threatening symptoms shortly after birth. Several variants have been characterized within the gene for lactase-phlorizin hydrolase (LCT) that are associated with CLD. Here, we analyze at the biochemical and cellular levels LCT mutants harboring the genetic variants p.Y1390*, p.E1612*, p.S1150Pfs*19, p.S1121L, p.R1587H, and p.S688P. Our data unequivocally demonstrate that these mutants are absolutely transport incompetent, some of which are readily degraded, and are enzymatically inactive. The current study contributes to and expands our understanding on the pathogenesis of CLD at the molecular level. [ABSTRACT FROM AUTHOR]

Abstract: Primary lactase deficiency (PLD), the physiological decline of lactase, is associated with the LC-13910C/T and LCT-22018G/A polymorphisms. PLD is the most common phenotype in humans and varies widely as a function of ethnicity. Israel is a multiethnic country. We analyzed the genetic frequencies of PLD in different Israeli ethnicities. Ethnicity-related frequencies were analyzed in 439 Israelis: Ashkenazi (n=96), Iraqi (n=96), Moroccan (n=96) Jews and Bedouin-Arabs (n=151). DNA was extracted from leukocytes; LCT-13910C/T, -22018G/A and -13915T/G (in Bedouin-Arabs) polymorphisms were analyzed by PCR-restriction fragment length polymorphism analysis. There was a significant association between ethnicity and genotype in both polymorphic LCT SNPs (-13910C/T and -22018). Prevalence of the CC (LCT-13910C/T) genotype associated with adult hypolactasia was 97%, 93%, 83% and 82% among Bedouin-Arabs and Iraqi, Ashkenazi and Moroccan Jews, respectively. The prevalence of the GG (LCT-22018G/A) adult hypolactasia genotype among those groups was identical to that of the CC genotype in each group, except for Iraqi-Jews, of which only 83% carried the GG genotype. The prevalence of heterozygous and homozygous genotypes associated with lactase persistence (CT, TT for -13910C/T and GA, AA for -22018G/A) was 3%, 7%, 17% and 18% and 3%, 17%, 17% and 18% for Bedouin-Arabs, Ashkenazi, Iraqi and Moroccan Jews, respectively. A significant correlation between SNPs was found. PLD prevalence is high among different ethnic groups in Israel and varies between ethnicities. The prevalence of the -13915*G allele, indicative of lactose persistence in African and Arab populations, was 41% in the Bedouin-Arabs group. Lactase persistence genotype prevalence was found to vary between Israeli ethnicities (4–18%). SNPs (-13910C/T and -22018) showed significant correlation in detecting genotype prevalence in Israeli Jews. We suggest adjusting nutritional recommendations accordingly. [Copyright &y& Elsevier]

Background. Adult-type hypolactasia (lactase non-persistence) is a common cause of gastrointestinal symptoms. Several DNA sequence variants have been identified for the lactase-persistence/non-persistence (LP/LNP), the most common being the C to T residing -13910 bp upstream of the lactase gene (LCT). We have analysed sequence variants of LP/LNP in subjects originating from Northern Russia. Methods. A total of 148 subjects with gastrointestinal complaints were genotyped covering about 400 bp around the -13910C/T variant using direct PCR-sequencing. All patients were interviewed about milk-related symptoms using the questionnaire. Disaccharidase activities were measured from intestinal biopsy specimens of the index person. Results. The prevalence of the -13910C/C genotype among 148 patients was 28.4%. A G to A variant residing 13914 bp upstream from the LCT gene (-13914G>A) was identified in one participant carrying the -13910C/C genotype. In two biopsy specimens her lactase activity was above the generally accepted cut off level for adult-type hypolactasia, 10U/g protein. Three other family members also carried the -13914G>A genotype. Among eight family members five had the LNP genotype -13910C/C. Conclusion. A rare variant G to A residing 13914 bp upstream of the LCT gene was identified in a subject carrying the more frequent variant -13910C/C. The -13914G>A variant in heterozygous state was associated with increased lactase activity, suggesting that the increased lactase activity is most likely to be associated with the -13914G>A variant. Further studies need to be done to confirm the functional role of this variant. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the frequency of the LCT*-13910C>T polymorphism associated with a high expression of lactase in the small intestine during adulthood, and to infer the lactase persistence and adult-type hypolactasia phenotypes among Euro-Brazilians and Mennonites from South Brazil.Materials and Methods: A sequence-specific PCR method to genotype the LCT*-13910C>T polymorphism in 292 Euro-Brazilians and 151 Mennonites (a group with European ancestry and a long history of endogamy) was developed. Using an exact test of population differentiation, the genotype and allele frequency between these and other Brazilian populations were compared.Results: The frequency of -13910*T was significantly higher among the Mennonites when compared to the Euro-Brazilian cohort (0.63 vs. 0.33, p < 0.000001). Accordingly, Mennonites had a higher prevalence of the lactase persistence genotype (88.1 vs. 55.5%, p < 0.000001). The distribution of -13910*T differed between Mennonites and all other Brazilian groups (p < 0.0001). The Euro-Brazilians from Curitiba displayed differences when compared to all other Brazilian groups (p < 0.0001), even to Euro-Brazilians from a different geographic region (p = 0.0003), but were similar to those from Porto Alegre (p = 0.2).Conclusion: Differences in the -13910*T-associated lactase persistence distribution among Euro-Brazilian groups reflect the ancestry and admixture of each particular group and should be considered for adult-type hypolactasia screening. [ABSTRACT FROM AUTHOR]

Background: Adult-type hypolactasia is characterized by the inability to digest lactose during adulthood, due to lactase (LCT) deficiency. It is usually diagnosed by the measurement of breath hydrogen increase after a lactose load (breath hydrogen test, BHT). A substitution of C to T at position –13910 bp upstream the LCT gene (rs4988235), in a regulatory region, was found to be strongly associated with the lactase persistence phenotype in North-European populations. Methods: We investigated the –13910 C/T polymorphism to determine LCT genotype distribution and to validate genetic testing for adult-type hypolactasia in a Southern European population. A total of 43 children referred for suspected lactose malabsorption were enrolled in the study, their parents and siblings (whole sample=112 individuals) also took the breath test, and all were enrolled for clinical monitoring and genotype determination. In addition, 125 unrelated blood donors from the same geographic area were genotyped for the calculation of allelic frequencies. The frequency of C/C genotypes was 70%. Results: The correlation between the C/C genotype (which should correspond to lactose non-digesters) and positive BHT in unrelated family founders was significant (χ2=16.7, p<0.002). The genetic test compared to the BHT had a sensitivity of 95% and 91% and a specificity of 48% and 55% in adults and children, respectively. Conclusions: Low specificity might be due to intrinsic limitations of the standard BHT or to other possible mutations, although no sequence variation was found upon sequencing a 253 bp fragment of the LCT regulatory region in asymptomatic individuals. Clin Chem Lab Med 2008;46:980–4. [ABSTRACT FROM AUTHOR]

Objective. Adult-type hypolactasia (AtH) can be diagnosed by genotyping in addition to functional tests or intestinal biopsy. The aims of this study were to estimate the prevalence of AtH by genotyping and to investigate whether AtH prevalence has changed in Sweden during the 20th century. Material and methods. Schoolchildren (n=690) born in 1983 and 1989, and elderly individuals (n=392) born between 1920 and 1932 were genotyped for AtH using Pyrosequencing technology. Results. The overall prevalence of AtH among children was 14.1%. The majority of children (92%, n=635) were Caucasians with genotype prevalences: CC, 61 (10%); CT, 259 (41%); TT, 307 (49%). The frequency of the mutated allele q was 0.300 in this cohort. The prevalence of AtH estimated from the Hardy-Weinberg equilibrium (HWE) (q 2), was 9.0% (95% CI: 6.7–11.2%). Eight percent (n=55) of the children were non-Caucasian; genotype prevalences were CC, 36 (66%); CT, 15 (27%); TT, 4 (7%). The prevalence of AtH in these children estimated from HWE was 62.5% (95% CI: 49.7–75.3%). The elderly subjects were all Caucasians. Their genotype prevalences were: CC, 20 (5%); CT, 166 (42%); TT, 206 (53%); the frequency of the mutated allele q was 0.262 and their AtH prevalence estimated from HWE was 6.8% (95% CI: 4.3–9.2%). Conclusions. The overall prevalence of AtH in children (14%) was higher than previously thought. Among Caucasians, higher figures were seen in children than in the elderly (9% versus 6.8%). The prevalence thus seems to be increasing and this may be due to the immigration of both non-Caucasian and Caucasian groups with a higher prevalence of AtH. [ABSTRACT FROM AUTHOR]

Congenital lactase deficiency (CLD) is a severe gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas. We initially assigned the CLD locus by linkage and linkage disequilibrium on 2q21 in 19 Finnish families. Here we report the molecular background of CLD via characterization of five distinct mutations in the coding region of the lactase (LCT) gene. Twenty-seven patients out of 32 (84%) were homozygous for a nonsense mutation, c.4170T→A (Y1390X), designated "Finmajor." Four rare mutations—two that result in a predicted frameshift and early truncation at S1666fsX1722 and S218fsX224 and two point mutations that result in substitutions Q268H and G1363S of the 1,927-aa polypeptide—confirmed the lactase mutations as causative for CLD. These findings facilitate genetic testing in clinical practice and enable genetic counseling for this severe disease. Further, our data demonstrate that, in contrast to common adult-type hypolactasia (lactose intolerance) caused by a variant of the regulatory element, the severe infancy form represents the outcome of mutations affecting the structure of the protein inactivating the enzyme. [ABSTRACT FROM AUTHOR]