title: Polymorphisms and mutations of human TMPRSS6 in iron deficiency anemia.
abstract: Male subjects with iron deficiency from the general population were examined for polymorphisms or sporadic mutations in TMPRSS6 to identify genetic risk factors for iron deficiency anemia. Three uncommon non-synonymous polymorphisms were identified, G228D, R446W, and V795I (allele frequencies 0.0074, 0.023 and 0.0074 respectively), of which the R446W polymorphism appeared to be overrepresented in the anemic population. In addition, three children with iron refractory iron deficiency anemia, and one sibling with iron responsive iron deficiency anemia were also examined for polymorphisms or sporadic mutations in TMPRSS6. Two children (family 1) were compound heterozygotes for a L674F mutation and a previously described splicing defect predicted to cause skipping of exon 13 (IVS13+1 G>A). One child from the second family was homozygous for a deletion (497T) causing a frameshift (L166X+36) and premature termination. The sibling and mother from the second family were compound heterozygotes for the L166X mutation and the uncommon R446W polymorphism. Although in vitro expression studies demonstrated that the R446W isoform was biologically similar to wildtype Tmprss6, clinical data indicate that the R446W produces a milder disease when carried in trans with severe mutation in Tmprss6. The four children carrying mutations in TMPRSS6 all exhibited inappropriately high urinary hepcidin levels for the degree of iron deficiency.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: E
authors.initials: E
authors.lastname: Beutler
authors.forename: C
authors.initials: C
authors.lastname: Van Geet
authors.forename: D M W M
authors.initials: DM
authors.lastname: te Loo
authors.forename: T
authors.initials: T
authors.lastname: Gelbart
authors.forename: K
authors.initials: K
authors.lastname: Crain
authors.forename: J
authors.initials: J
authors.lastname: Truksa
authors.forename: P L
authors.initials: PL
authors.lastname: Lee
mesh_terms: D000368:Aged; D019943:Amino Acid Substitution / Q000235:genetics; D018798:Anemia, Iron-Deficiency / Q000235:genetics*; D000753:Anemia, Refractory / Q000235:genetics*; D023181:Antimicrobial Cationic Peptides / Q000097:blood / Q000652:urine; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency; D056945:Hep G2 Cells; D064451:Hepcidins; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D011110:Polymorphism, Genetic; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D044465:White People
chemical_list: D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D008565:Membrane Proteins; D012697:Serine Endopeptidases; C504318:TMPRSS6 protein, human; C467801:matriptase 2