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Identification of a human mutation of DMT1 in a patient with microcytic anemia and iron overload
MP Mims, Y Guan, D Pospisilova, M Priwitzerova, K Indrak, P Ponka, V Divoky, JT Prchal
Jazyk angličtina Země Spojené státy americké
Grantová podpora
NM6739
MZ0
CEP - Centrální evidence projektů
Digitální knihovna NLK
Plný text - Část
Zdroj
NLK
Free Medical Journals
od 1946 do Před 1 rokem
Freely Accessible Science Journals
od 1946 do Před 1 rokem
Open Access Digital Library
od 1946-01-01
Open Access Digital Library
od 1946-01-01
ROAD: Directory of Open Access Scholarly Resources
- MeSH
- biopsie MeSH
- exony genetika MeSH
- hepatocyty patologie MeSH
- hypochromní anemie genetika komplikace patologie MeSH
- játra patologie MeSH
- jednonukleotidový polymorfismus genetika MeSH
- krysa rodu rattus MeSH
- Kupfferovy buňky patologie MeSH
- lidé MeSH
- messenger RNA genetika MeSH
- modely nemocí na zvířatech MeSH
- mutace MeSH
- myši MeSH
- přetížení železem genetika komplikace patologie MeSH
- transkripční faktory MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
Divalent metal transporter 1 (DMT1) is a transmembrane protein crucial for duodenal iron absorption and erythroid iron transport. DMT1 function has been elucidated largely in studies of the mk mouse and the Belgrade rat, which have an identical single nucleotide mutation of this gene that affects protein processing, stability, and function. These animals exhibit hypochromic microcytic anemia due to impaired intestinal iron absorption, and defective iron utilization in red cell precursors. We report here the first human mutation of DMT1 identified in a female with severe hypochromic microcytic anemia and iron overload. This homozygous mutation in the ultimate nucleotide of exon 12 codes for a conservative E399D amino acid substitution; however, its pre-dominant effect is preferential skipping of exon 12 during processing of pre-messenger RNA (mRNA). The lack of full-length mRNA would predict deficient iron absorption in the intestine and deficient iron utilization in erythroid precursors; however, unlike the animal models of DMT1 mutation, the patient is iron overloaded. This does not appear to be due to up-regulation of total DMT1 mRNA. DMT1 protein is easily detectable by immunoblotting in the patient's duodenum, but it is unclear whether the protein is properly processed or targeted.
Department of Biology Faculty of Medicine Palacky University Olomouc Czech Republic
Department of hemato oncology Faculty of Medicine Palacky University Olomouc Czech Republic
Department of Pediatrics Faculty of Medicine Palacky University Olomouc Czech Republic
Literatura
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- $a Literatura
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- $a Divalent metal transporter 1 (DMT1) is a transmembrane protein crucial for duodenal iron absorption and erythroid iron transport. DMT1 function has been elucidated largely in studies of the mk mouse and the Belgrade rat, which have an identical single nucleotide mutation of this gene that affects protein processing, stability, and function. These animals exhibit hypochromic microcytic anemia due to impaired intestinal iron absorption, and defective iron utilization in red cell precursors. We report here the first human mutation of DMT1 identified in a female with severe hypochromic microcytic anemia and iron overload. This homozygous mutation in the ultimate nucleotide of exon 12 codes for a conservative E399D amino acid substitution; however, its pre-dominant effect is preferential skipping of exon 12 during processing of pre-messenger RNA (mRNA). The lack of full-length mRNA would predict deficient iron absorption in the intestine and deficient iron utilization in erythroid precursors; however, unlike the animal models of DMT1 mutation, the patient is iron overloaded. This does not appear to be due to up-regulation of total DMT1 mRNA. DMT1 protein is easily detectable by immunoblotting in the patient's duodenum, but it is unclear whether the protein is properly processed or targeted.
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