Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2)‏ by Achille Iolascon, Maria d'Apolito, Veronica.

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Microcytic anemia and hepatic iron overload in a child with compound heterozygous mutations in DMT1 (SCL11A2)‏ by Achille Iolascon, Maria d'Apolito, Veronica Servedio, Flora Cimmino, Antonio Piga, and Clara Camaschella Blood Volume 107(1):349-354 January 1, 2006 ©2006 by American Society of Hematology

Micrographs of liver biopsy sample showing the entity and the distribution of iron. Micrographs of liver biopsy sample showing the entity and the distribution of iron. Staining technique: Perl Prussian blue. (A) The liver has normal architecture. Iron is heavily distributed in zone 1, whereas zone 2 appears less loaded. Original magnification, × 25. (B) Most hepatocytes were massively loaded by hemosiderin (Sciot grading 3) and by Kupffer cells to a minor extent (Sciot grading 2). Original magnification, × 200. Images were observed using an Axioplan 2 microscope (Zeiss, Göttingen, Germany) and Plan-Apochromat 4×/0.10 numeric aperture (NA) and 20×/0.40 NA objectives. Images were captured using a Nikon Coolpix 950 (Nikon, Melville, NY), and processed with ACDsee version 6.0 software (ACD Systems, Saanichton, BC, Canada). Achille Iolascon et al. Blood 2006;107:349-354 ©2006 by American Society of Hematology

Identification of the DMT1 mutations in the proband. Identification of the DMT1 mutations in the proband. (A) Partial sequence of intron 4-exon 5 junction of the proband and wild-type (WT) DNA identifying the c.310-3_5del CTT mutation (underlined). The abnormality in the consensus sequence of the acceptor splice site is shown on the right. The dinucleotide acceptor site is in bold. (B) Sequence analysis of the DNA region encompassing exon 13 showing the heterozygous C>T transition at position 1246, causing a p. R416C mutation. (C) ClustalW alignment of the amino acid sequences of NRAMP2 (DMT1) and NRAMP1 orthologs from different species, showing complete conservativeness of the R416 residue (boxed). Achille Iolascon et al. Blood 2006;107:349-354 ©2006 by American Society of Hematology

Analysis of the effect of c.310-3_5del CTT deletion. Analysis of the effect of c.310-3_5del CTT deletion. (A) Amplification of the exon 4-6 region of DMT1 mRNA from whole blood. cDNA was synthesized as described in “Patient, materials, and methods.” The exon 4-6 region of DMT1 cDNA was amplified by PCR, and the product was separated on 1% agarose gel. (lane 1) 1-kb DNA ladder. (lane 2) I-1. (lane 3) Proband. (lane 4) I-2. (lane 5) Healthy control. (lane 6) No template control. The top band measures 298 bp, and the bottom band in lanes 2 and 3 measures 178 bp. (B) Sequencing of PCR product of the 178-bp band (A) of II-1, resulting in exon 5 skipping and a 40 amino acid loss in the protein. (C) Schematic representation of DMT1 exon 5 skipping in the proband. Achille Iolascon et al. Blood 2006;107:349-354 ©2006 by American Society of Hematology

Detection of DMT1 protein in PBMCs Detection of DMT1 protein in PBMCs. Total PBMC extracts were prepared as described: 80 μg total protein was loaded into each lane and was separated by SDS-PAGE on a 10% acrylamide gel followed by transfer to PVDF membranes. Detection of DMT1 protein in PBMCs. Total PBMC extracts were prepared as described: 80 μg total protein was loaded into each lane and was separated by SDS-PAGE on a 10% acrylamide gel followed by transfer to PVDF membranes. Membranes were incubated with anti-DMT1-NT antibody (A) and with β-actin antibody as an internal loading control (B). Samples in the different lanes are indicated. Sizes (in kDa) are on the right. Achille Iolascon et al. Blood 2006;107:349-354 ©2006 by American Society of Hematology