title: Congenital lactose intolerance is triggered by severe mutations on both alleles of the lactase gene.
abstract: BACKGROUND
  Congenital lactase deficiency (CLD) is a rare severe autosomal recessive disorder, with symptoms like watery diarrhea, meteorism and malnutrition, which start a few days after birth by the onset of nursing. The most common rationales identified for this disorder are missense mutations or premature stop codons in the coding region of the lactase-phlorizin hydrolase (LPH) gene. Recently, two heterozygous mutations, c.4419C > G (p.Y1473X) in exon 10 and c.5387delA (p.D1796fs) in exon 16, have been identified within the coding region of LPH in a Japanese infant with CLD.
  
  
  METHODS
  Here, we investigate the influence of these mutations on the structure, biosynthesis and function of LPH. Therefore the mutant genes were transiently expressed in COS-1 cells.
  
  
  RESULTS
  We show that both mutant proteins are mannose-rich glycosylated proteins that are not capable of exiting the endoplasmic reticulum. These mutant proteins are misfolded and turnover studies show that they are ultimately degraded. The enzymatic activities of these mutant forms are not detectable, despite the presence of lactase and phlorizin active sites in the polypeptide backbone of LPH-D1796fs and LPH-Y1473X respectively. Interestingly, wild type LPH retains its complete enzymatic activity and intracellular transport competence in the presence of the pathogenic mutants suggesting that heterozygote carriers presumably do not show symptoms related to CLD.
  
  
  CONCLUSIONS
  Our study strongly suggests that the onset of severe forms of CLD is elicited by mutations in the LPH gene that occur in either a compound heterozygous or homozygous pattern of inheritance.
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Buenteweg 17, D-30559, Hannover, Germany. lena.diekmann@tiho.hannover.de.
authors.forename: Lena
authors.initials: L
authors.lastname: Diekmann
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Buenteweg 17, D-30559, Hannover, Germany. katrin.pfeiffer@tiho.hannover.de.
authors.forename: Katrin
authors.initials: K
authors.lastname: Pfeiffer
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Buenteweg 17, D-30559, Hannover, Germany. hassan.naim@tiho.hannover.de.
authors.forename: Hassan Y
authors.initials: HY
authors.lastname: Naim
mesh_terms: D000818:Animals; D019556:COS Cells; D002239:Carbohydrate Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics*; D002522:Chlorocebus aethiops; D005819:Genetic Markers; D006579:Heterozygote; D006801:Humans; D043322:Lactase / Q000172:deficiency* / Q000235:genetics; D010694:Lactase-Phlorizin Hydrolase / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D007787:Lactose Intolerance / Q000201:enzymology / Q000235:genetics*; D009154:Mutation
chemical_list: D005819:Genetic Markers; D043322:Lactase; D010694:Lactase-Phlorizin Hydrolase