title: Molecular pathogenicity of novel sucrase-isomaltase mutations found in congenital sucrase-isomaltase deficiency patients.
abstract: Congenital sucrase-isomaltase deficiency (CSID) is a genetic disorder associated with mutations in the sucrase-isomaltase (SI) gene. The diagnosis of congenital diarrheal disorders like CSID is difficult due to unspecific symptoms and usually requires invasive biopsy sampling of the intestine. Sequencing of the SI gene and molecular analysis of the resulting potentially pathogenic SI protein variants may facilitate a diagnosis in the future. This study aimed to categorize SI mutations based on their functional consequences.
  
  
  
  cDNAs encoding 13 SI mutants were expressed in COS-1 cells. The molecular pathogenicity of the resulting SI mutants was defined by analyzing their biosynthesis, cellular localization, structure and enzymatic functions.
  
  
  
  Three biosynthetic phenotypes for the novel SI mutations were identified. The first biosynthetic phenotype was defined by mutants that are intracellularly transported in a fashion similar to wild type SI and with normal, but varying, levels of enzymatic activity. The second biosynthetic phenotype was defined by mutants with delayed maturation and trafficking kinetics and reduced activity. The third group of mutants is entirely transport incompetent and functionally inactive.
  
  
  
  The current study unraveled CSID as a multifaceted malabsorption disorder that comprises three major classes of functional and trafficking mutants of SI and established a gradient of mild to severe functional deficits in the enzymatic functions of the enzyme.
  
  
  
  This novel concept and the existence of mild consequences in a number of SI mutants strongly propose that CSID is an underdiagnosed and a more common intestinal disease than currently known.
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Germany.
authors.forename: Birthe
authors.initials: B
authors.lastname: Gericke
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Germany.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Amiri
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
authors.forename: C Ronald
authors.initials: CR
authors.lastname: Scott
authors.affiliation: Department of Physiological Chemistry, University of Veterinary Medicine Hannover, Germany. Electronic address: hassan.naim@tiho-hannover.de.
authors.forename: Hassan Y
authors.initials: HY
authors.lastname: Naim
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002239:Carbohydrate Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism; D002522:Chlorocebus aethiops; D006801:Humans; D009154:Mutation; D021381:Protein Transport; D013394:Sucrase-Isomaltase Complex / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism
chemical_list: D013394:Sucrase-Isomaltase Complex
keywords: Carbohydrate malabsorption; Genetic intestinal disorders; Protein trafficking; Sucrase-isomaltase