title: A mutation in the insulin receptor that impairs proreceptor processing but not insulin binding.
abstract: Here we report the identification of a new mutation in the alpha-chain of the insulin receptor, changing Trp412 into Ser using DNA from consanguineous parents who gave birth to a child with leprechaunism. The mutant receptor was expressed stably in CHO and transiently in COS-1 cells. It was found that the Ser412 mutant is not cleaved into alpha- and beta-subunits and remains as a 210-kDa proreceptor at an intracellular site. This property of the mutant receptor is in line with the observed decreased insulin binding to the parental fibroblasts. Cross-linking experiments show that the Ser412 proreceptor is able to bind insulin with an affinity comparable to that of the wild-type alpha-chain. Despite its capacity to bind insulin, the mutant receptor is not autophosphorylated. We postulate that the patient was homozygous for the Trp412-->Ser mutation and that the mutation was responsible for the leprechaun phenotype. This is the first description of a transport-defective receptor with the mutation outside the tetrabasic processing site and a functional insulin binding domain. The ability of the Ser412 mutant to bind insulin in cross-linking experiments suggests that the impaired transport of the proreceptor to the cell surface is the primary cause for the binding defect to intact cells.
authors.affiliation: Department of Medical Biochemistry, Sylvius Laboratories, State University, Leiden, The Netherlands.
authors.forename: E R
authors.initials: ER
authors.lastname: van der Vorm
authors.forename: A
authors.initials: A
authors.lastname: Kuipers
authors.forename: S
authors.initials: S
authors.lastname: Kielkopf-Renner
authors.forename: H M
authors.initials: HM
authors.lastname: Krans
authors.forename: W
authors.initials: W
authors.lastname: Möller
authors.forename: J A
authors.initials: JA
authors.lastname: Maassen
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006031:Glycosylation; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000235:genetics; D008715:Methionine; D008969:Molecular Sequence Data; D009154:Mutation; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics*; D011972:Receptor, Insulin / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D011498:Protein Precursors; D008715:Methionine; D011972:Receptor, Insulin