Expression of hepcidin, a key regulator of intestinal iron absorption, can be induced in vitro by several bone morphogenetic proteins (BMPs), including BMP2, BMP4 and BMP9 (refs. 1,2). However, in contrast to BMP6, expression of other BMPs is not regulated at the mRNA level by iron in vivo, and their relevance to iron homeostasis is unclear. We show here that targeted disruption of Bmp6 in mice causes a rapid and massive accumulation of iron in the liver, the acinar cells of the exocrine pancreas, the heart and the renal convoluted tubules. Despite their severe iron overload, the livers of Bmp6-deficient mice have low levels of phosphorylated Smad1, Smad5 and Smad8, and these Smads are not significantly translocated to the nucleus. In addition, hepcidin synthesis is markedly reduced. This indicates that Bmp6 is critical for iron homeostasis and that it is functionally nonredundant with other members of the Bmp subfamily. Notably, Bmp6-deficient mice retain their capacity to induce hepcidin in response to inflammation. The iron burden in Bmp6 mutant mice is significantly greater than that in mice deficient in the gene associated with classical hemochromatosis (Hfe), suggesting that mutations in BMP6 might cause iron overload in humans with severe juvenile hemochromatosis for which the genetic basis has not yet been characterized.

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Diversity in 39 HLA-A, -B, and -C molecules is derived from 20 amino acid positions of high variability and 71 positions of low variability. Variation in the structurally homologous a, and a2 domains is distinct and may correlate with partial segregation of peptide and T-cell receptor binding functions. Comparison of 15 HLA-A with 20 HLA-B molecules reveals considerable locus-specific character, due primarily to differences at polymorphic residues. The results indicate that genetic exchange between alleles of the same locus has been a more important mechanism in the generation of HLA-A, -B, and -C diversity than genetic exchange events between alleles of different loci.Class I major histocompatibility complex glycoproteins are peptide-binding proteins that present processed antigens to cytotoxic T lymphocytes. The genes coding for these molecules are the most polymorphic loci known in higher vertebrates and for humans a total of 19 HLA-A, 37 HLA-B, and 8 HLA-C molecules have been defined (1). Although the basic features of class I molecules are well defined (2), accumulation of allelic sequences has been slow. The paucity of sequences has limited our understanding of the scope of the polymorphism, its function, and its generation. We present here a comparison of 39 HLA-A, -B, and -C sequences and a general assessment of their patterns of diversity. MATERIALS AND METHODSGenomic clones encoding HLA-A1, -B8, -B14, -B18, -Bw4l, -Bw42, -B44.2, -Bw65, and -Cw2.2 were isolated from the following cell lines: S. Gar (HLA-Aw24,3;B18,w41;Cw6), BB (HLA-Aw68.2,30;Bw42,w6S), FMB (HLA-AJ,32;$44,w57; Cw5,w6), MRWC (HLA-A2,32$JA,27;Cw2), MVL (HLAAw32;B27;Cw2), and LCL721 (HLA-Ai,2$.i,5). The cloned genes are underlined. Construction of libraries, isolation and identification of genes, and sequencing of genes with exonspecific oligonucleotide primers were as described (3). Genomic clones encoding HLA-A1 and HLA-B8 were kindly provided by H. T. Orr (University of Minnesota) (4).RESULTS AND DISCUSSION Variability in HLA-A, -B, and -C Molecules. Genes encoding HLA-A1, -B8, -B14, -B18, -B44, -Bw4l, -Bw42, -Bw65, and -Cw2 were isolated, and the exons were sequenced. The sequences of the HLA-B44 and HLA-Cw2 proteins each differ by 3 amino acids from identically typed molecules isolated from other cell lines (5, 6). These represent distinct subtypes, and we have designated them as HLA-B44.2 and HLA-Cw2.2 compared to HLA-B44.1 and HLA-Cw2.1 for the published sequences (5, 6). (a,, a2, and a3) that interact with antigenic peptides, the T-cell receptor, and the CD8 molecule. As single residues predominate at most positions, a consensus sequence can be made (Fig. 1). Individual molecules differ from the consensus by [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30] residues, showing all have considerably diverged from a common ancestor.Without knowing the total number of alleles, it is difficult to predict how many sequences are required to gain an accurate description of HLA-A, -B, and -C polymorphism...