Year: 2006
Type: dissertation
Study design: Observational Study
Abstract: Congenital lactase deficiency (CLD) (MIM 223000) is a rare autosomal recessive gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas.The CLD locus was previously assigned by linkage and linkage disequilibrium analyses on 2q21 in 19 Finnish families.In this study, the molecular background of this disorder is reported.The CLD locus was refined in 32 CLD patients in 24 families by using microsatellite and single nucleotide polymorphism (SNP) haplotypes.Mutation analyses were performed by direct sequencing.We identified 5 distinct mutations in the lactase (LCT) gene, encoding the enzyme that hydrolyzes lactose in the intestinal lumen.Twenty-seven patients out of thirty-two (84%) were homozygous for a nonsense mutation, c.4170T→A (Y1390X, designated as Fin major ).In addition, four rare mutations were detected two of which, a four-nucleotide deletion (c.4998_5001delTGAG) and a two-nucleotide deletion (c.653_654delCT), predicted a frameshift and protein truncation at S1666fsX1722 and S218fsX224 of the 1927 amino acid polypeptide, respectively.Two point mutations, c.804G→C and c.4087G→A, would result in amino acid substitutions Q268H and G1363S, respectively.Five patients were compound heterozygous carrying the Fin major mutation and one of the four minor mutations.These findings facilitate genetic testing of CLD in clinical practice and enable genetic counseling.The present data also provide the basis for detailed characterization of the molecular pathogenesis of this disorder.Adult-type hypolactasia (MIM 223100) (lactase non-persistence, lactose intolerance) is an autosomal recessive gastrointestinal condition that is a result of a decline in the activity of lactase in the intestinal lumen after weaning.Adult-type hypolactasia is considered to be a normal phenomenon among mammals and symptoms are remarkably milder than experienced in CLD.Recently, a variant C/T -13910 was shown to associate with the adult-type hypolactasia trait, locating 13.9 kb upstream of the LCT gene (Enattah et al. 2002).In this study, the functional significance of the C/T -13910 variant was determined by studying the LCT mRNA levels in intestinal biopsy samples in children and adults with different genotypes.Intestinal biopsy samples were taken from 15 children or adolescents and from 52 adults with abdominal complaints.The expression of LCT mRNA was demonstrated in patients heterozygous for the C/T -13910 variant and an informative expressed SNP located in the coding region of LCT.RT-PCR followed by solid-phase minisequencing was applied to determine the relative expression levels of the LCT alleles using an informative SNP located in exon 1.In children, the C -13910 allele was observed to be downregulated after five years of age in parallel with lactase enzyme activity.The expression of the LCT mRNA in the intestinal mucosa in individuals with the T -13910 A -22018 alleles was 11.5 times higher than that found in individuals with the C -13910 , G -22018 alleles.These findings suggest that the C/T -13910 associated with adult-type hypolactasia is associated with the transcriptional regulation of the LCT gene.The presence of the T -13910 A -22018 allele also showed significant elevation lactase activity.Galactose, the hydrolysing product of the milk sugar lactose, has been hypothesized to be poisonous to ovarian epithelial cells.Hence, consumption of dairy products and lactase persistence has been proposed to be a risk factor for ovarian carcinoma.To investigate whether lactase persistence is related to the risk of ovarian carcinoma the C/T -13910 genotype was determined in a cohort of 782 women with ovarian carcinoma.The C/T -13910 genotype was determined by the solid-phase minisequencing method from 327 Finnish, 303 Polish, 152 Swedish patients and 938 Finnish, 296 Polish and 97 Swedish healthy subjects serving as controls.Lactase persistence did not associate significantly with the risk for ovarian carcinoma in the Finnish (OR 0.77, 95% CI, 0.57-1.05,p=0.097), in the Polish (OR 0.95, 95% CI, 0.68-1.33,p=0.75), or in the Swedish populations (OR 1.63, 95% CI, 0.65-4.08,p=0.29).The findings do not support the hypothesis that lactase persistence increases the risk for ovarian carcinoma.
Source: Työväentutkimus Vuosikirja
Author: Mikko Kuokkanen
Language: English
Subfield: Gastroenterology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funder: Helsingin Yliopisto
OpenAlex ID: W593087754