International Mammalian Genome Society

The 16th International Mouse Genome Conference (2002)

Plenary Presentations * Oral Presentations *
Poster Presentations: Complex Genetics and Disease Modifiers * Developmental Genetics * Functional Genomics * Gene Discovery * Genetic Manipulations to Alter Gene Function * Mouse Models: Human Disease and Pharmacogenetics * Sequence Annotation and Comparative Analysis of Genomes *
Attendees * Sponsors * Table of Contents * Photographs * Awards

Oral Presentation

Monday 18 November

11:00 - 11:15 HRS

MICE HEMIZYGOUS FOR ENU-INDUCED MUTATIONS AT THE FIT1 LOCUS HAVE DNA SEQUENCE AND STRUCTURAL ALTERATIONS IN PICALM, A GENE FOR A CLATHRIN-ASSEMBLY PROTEIN

M Klebig
The University of Tennessee-Knoxville & Oak Ridge National Laboratory

Co-Authors: 1) Potter M, 1, 3) Johnson E, 1, 2) Hill M, 2) Kerley M, 1) Rainwater L, 1, 2) Rinchik EM
Institutions: 1) The University of Tennessee-Knoxville,  2) Oak Ridge National Laboratory,  3) Current address:  Lexicon Genetics, Inc.

Mice hemi- or homozygous for any of five ENU-induced mutations at the fit1 locus in Chr 7 are characterized by anemia, other hematopoietic abnormalities, growth retardation, and shortened lifespan.  Additional study of an intermediate allele, fit14226SB, demonstrated microcytic hypochromic anemia, abnormal iron uptake and transport, scoliosis, and lumbar vertebral abnormalities.  The sequence of a BAC clone co-mapping with fit1 within the albino (Tyr) deletion complex revealed it contained the mouse homolog of the human PICALM gene (11q14), which encodes a clathrin-assembly protein thought to be important for clathrin-mediated endocytosis.  The human PICALM gene has also been repeatedly associated with a t(10;11)(p12-p13;q14-q21) translocation found in some leukemias (both ALL and AML) and lymphomas, where it forms a fusion transcript with the putative transcription factor AF10 on Chr 10.  The location of the mouse Picalm gene, and the fact that clathrin-mediated endocytosis is an important mechanism of iron uptake and transport, suggested Picalm as a good candidate for fit1.  We have identified Picalm mutations in three of the five fit1 alleles to date, and are continuing to analyze the potentially complex alternative splicing pattern of the gene.  The defects identified in the Picalm/fit1 mutants indicate it is a unique microcytic hypochromic anemia model, as well as a model for the study of scoliosis and of the relationships between cellular transport, iron metabolism, and bone growth. [Research sponsored by the Office of Biological and Environmental Research, US Department of Energy under contract DE-AC05-00OR22725 with UT-Battelle, LLC.]