Mc5

Marsh, Dave

doi:10.1093/gmo/9781561592630.article.46207

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“…The location of the mouse Picalm gene, and the fact that clathrin͞A P2-mediated endocytosis of the transferrin͞ transferrin-receptor complex from the plasma membrane is the main mechanism of iron uptake into most cells (28,29), suggested that Picalm was a good candidate for fit1, the only locus associated with severe anemia that was identified in this mutagenized chromosomal region (2,8). Thus, we first assembled a composite mouse Picalm cDNA sequence of Ϸ3.6 kb ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Mutations in the clathrin-assembly gene Picalm are responsible for the hematopoietic and iron metabolism abnormalities in fit1 mice

Klebig

Wall

Potter

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

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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 (fit1 4R ). We report that fit1 4R , as well as the most severe fit1 5R 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 Picalm fit1-5R and Picalm fit1-4R 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 Picalm fit1 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.

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Section: Resultsmentioning

confidence: 99%