title: Mutations in the clathrin-assembly gene Picalm are responsible for the hematopoietic and iron metabolism abnormalities in fit1 mice.
abstract: Recessive N-ethyl-N-nitrosourea (ENU)-induced mutations recovered at the fitness-1 (fit1) locus in mouse chromosome 7 cause hematopoietic abnormalities, growth retardation, and shortened life span, with varying severity of the defects in different alleles. Abnormal iron distribution and metabolism and frequent scoliosis have also been associated with an allele of intermediate severity (fit14R). We report that fit14R, as well as the most severe fit15R allele, are nonsense point mutations in the mouse ortholog of the human phosphatidylinositol-binding clathrin assembly protein (PICALM) gene, whose product is involved in clathrin-mediated endocytosis. A variety of leukemias and lymphomas have been associated with translocations that fuse human PICALM with the putative transcription factor gene AF10. The Picalmfit1-5R and Picalmfit1-4R mutations are splice-donor alterations resulting in transcripts that are less abundant than normal and missing exons 4 and 17, respectively. These exon deletions introduce premature termination codons predicted to truncate the proteins near the N and C termini, respectively. No mutations in the genes encoding Picalm, clathrin, or components of the adaptor protein complex 2 (AP2) have been previously described in which the suite of disorders present in the Picalmfit1 mutant mice is apparent. These mutants thus provide unique models for exploring how the endocytic function of mouse Picalm and the transport processes mediated by clathrin and the AP2 complex contribute to normal hematopoiesis, iron metabolism, and growth.
authors.affiliation: Department of Biochemistry and Cellular and Molecular Biology, University of Tennessee, Knoxville, TN 37996, USA. klebigml@ornl.gov
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Klebig
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Wall
authors.forename: Mark D
authors.initials: MD
authors.lastname: Potter
authors.forename: Erica L
authors.initials: EL
authors.lastname: Rowe
authors.forename: Donald A
authors.initials: DA
authors.lastname: Carpenter
authors.forename: Eugene M
authors.initials: EM
authors.lastname: Rinchik
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D018389:Codon, Nonsense; D004705:Endocytosis; D005091:Exons / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics*; D007501:Iron / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains / Q000235:genetics*; D008969:Molecular Sequence Data; D034041:Monomeric Clathrin Assembly Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D020125:Mutation, Missense; D017354:Point Mutation; D022821:RNA Splice Sites / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D034041:Monomeric Clathrin Assembly Proteins; C439003:PICALM protein, human; D022821:RNA Splice Sites; D007501:Iron