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A mutation in Sec15l1 causes anemia in hemoglobin deficit (hbd) mice

Nature Genetics volume 37, pages 1270–1273 (2005)Cite this article

Abstract

Hemoglobin deficit (hbd) mice carry a spontaneous mutation that impairs erythroid iron assimilation but does not cause other defects. Normal delivery of iron to developing erythroid precursors is highly dependent on the transferrin cycle. Through genetic mapping and complementation experiments, we show that the hbd mutation is an in-frame deletion of a conserved exon of the mouse gene Sec15l1, encoding one of two Sec15 proteins implicated in the mammalian exocyst complex. Sec15l1 is linked to the transferrin cycle through its interaction with Rab11, a GTPase involved in vesicular trafficking. We propose that inactivation of Sec15l1 alters recycling of transferrin cycle endosomes and increases the release of transferrin receptor exocytic vesicles. This in turn decreases erythroid iron uptake. Determining the molecular basis of the hbd phenotype provides new insight into the intricate mechanisms necessary for normal erythroid iron uptake and the function of a mammalian exocyst protein.

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Figure 1: Phenotype of hbd mice.
Figure 2: Analysis of Sec15l1 and Sec15l2 expression.
Figure 3: Insertional mutagenesis of Sec15l1.

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Acknowledgements

We thank C. Roy and T. Holm for sharing unpublished data; A. Donovan, J. Glaven, D. Wrighting and R. Ohgami discussing experiments and commenting on the manuscript; G. Gilliland for assistance with BMT experiments; and Y. Fujiwara for blastocyst injections. This work was supported by a March of Dimes research grant and a grant from the US National Institutes of Health to N.C.A. NCA is also an investigator of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Children's Hospital Boston, Karp Family Research Laboratories RM 8-125, Boston, 02115-5737, Massachusetts, USA

    Jackie E Lim, Ou Jin, Carolyn Bennett, Fudi Wang, Cameron C Trenor III & Nancy C Andrews

  2. Harvard Medical School, Boston, Massachusetts, USA

    Jackie E Lim, Carolyn Bennett, Fudi Wang, Cameron C Trenor III, Mark D Fleming & Nancy C Andrews

  3. Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts, USA

    Kelly Morgan

  4. Department of Pathology, Children's Hospital Boston, Boston, Massachusetts, USA

    Mark D Fleming

  5. Howard Hughes Medical Institute, Boston, Massachusetts, USA

    Nancy C Andrews

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  1. Jackie E Lim
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Correspondence to Nancy C Andrews.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Table 1

Oligonucleotides used as PCR primers for analysis of Sec15l1. (PDF 57 kb)

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Lim, J., Jin, O., Bennett, C. et al. A mutation in Sec15l1 causes anemia in hemoglobin deficit (hbd) mice. Nat Genet 37, 1270–1273 (2005). https://doi.org/10.1038/ng1659

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