Hypomorphic variants of lactase-phlorizin hydrolase in congenital lactase deficiency are trafficking incompetent and functionally inactive

Biochim Biophys Acta Mol Basis Dis. 2022 Apr 1;1868(4):166338. doi: 10.1016/j.bbadis.2022.166338. Epub 2022 Jan 8.

Abstract

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.

Keywords: Biosynthesis; Carbohydrate malabsorption; Congenital lactase deficiency; Enzyme function; LCT gene; Mutations; Protein trafficking.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • COS Cells
  • Carbohydrate Metabolism, Inborn Errors / genetics
  • Carbohydrate Metabolism, Inborn Errors / pathology*
  • Chlorocebus aethiops
  • Humans
  • Lactase / deficiency*
  • Lactase / genetics
  • Lactase-Phlorizin Hydrolase / chemistry
  • Lactase-Phlorizin Hydrolase / genetics*
  • Lactase-Phlorizin Hydrolase / metabolism
  • Mutagenesis, Site-Directed
  • Mutation, Missense
  • Protein Folding
  • Protein Transport

Substances

  • Lactase
  • Lactase-Phlorizin Hydrolase

Supplementary concepts

  • Lactase Deficiency, Congenital