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Molecular and cellular analysis of intestinal lactase‐phlorizin hydrolase gene variants unravel a heterogeneous pathogenic pattern of congenital lactase deficiency
Author(s) -
Marten Lara M.,
Wanes Dalanda,
Santer René,
Naim Hassan Y.
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.05125
Subject(s) - lactase , phenotype , heterozygote advantage , biology , mutant , sucrase , wild type , gene , genetics , mutation , brush border , compound heterozygosity , genotype , lactose intolerance , missense mutation , microbiology and biotechnology , lactose , biochemistry , enzyme , vesicle , membrane
Congenital lactase deficiency (CLD) is a rare autosomal recessive genetic disorder, leading to a dysfunctional lactase‐phlorizin hydrolase (LPH). LPH is a ß‐galactosidase located in the intestinal brush border membrane and indispensable for lactose digestion. Impaired LPH‐function results in severe symptoms within a few days after birth with the onset of nursing. The symptoms include watery diarrhea and consequently dehydration, leading to potential life‐threatening disease of the newborn. Several mutations in the coding region of LPH have been characterized, occurring in homozygote or compound heterozygote patterns of inheritance. The basis of the genotype‐phenotype relationship in CLD on a molecular and cellular level has not been studied in details. Here we analyze the influence of the mutations p.S688P, p.E1612X, p.S1121L, that have been identified in patients from different ethnic groups, on the structure, trafficking and function of the LPH protein. For this purpose, LPH‐mutants were generated by site‐directed mutagenesis and transiently expressed in COS‐1 cells. Additionally we concluded studies regarding the interaction of these mutants with the wild‐type‐LPH protein. The results reveal phenotypic variations in the protein trafficking of the mutants between the ER and the Golgi. Additionally, the LPH‐mutant harboring the mutation p.S688P showed residual lactose digesting capacity. These variations implicate possible clinical correlation as for example different course and severity of disease. These data are relevant for the further understanding of CLD, potential impact for heterozygote mutation carriers and possible invention of treatment strategies, as for example protein stabilization through chaperones. Support or Funding Information Intramural funds, University of Veterinary Medicine Hannover