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Fine-mapping and genetic analysis of the loci affecting hepatic iron overload in mice.

ABSTRACT: The liver, as the major organ for iron storage and production of hepcidin, plays pivotal roles in maintaining mammalian iron homeostasis. A previous study showed that Quantitative Trait Loci (QTLs) on chromosome 7 (Chr7) and 16 (Chr16) may control hepatic non-heme iron overload in an F2 intercross derived from C57BL/6J (B6) and SWR/J (SWR) mice. In this study, we aimed to validate the existence of these loci and identify the genes responsible for the phenotypic variations by generating congenic mice carrying SWR chromosome segments expanding these QTLs (D7Mit68-D7Mit71 and D16Mit125-D16Mit185, respectively). We excluded involvement of Chr7 based on the lack of iron accumulation in congenic mice. In contrast, liver iron accumulation was observed in Chr16 congenic mice. Through use of a series of subcongenic murine lines the interval on Chr16 was further fine-mapped to a 0.8 Mb segment spanning 11 genes. We found that the mRNA expression pattern in the liver remained unchanged for all 11 genes tested. Most importantly, we detected 4 missense mutations in 3 candidate genes including Sidt1 (P172R), Spice1(R708S), Boc (Q1051R) and Boc (S450-insertion in B6 allele) in the liver of SWR homozygous congenic mice. To further delineate potential modifier gene(s), we reconstituted seven candidate genes, Sidt1, Boc, Zdhhc23, Gramd1c, Atp6v1a, Naa50 and Gtpbp8, in mouse liver through hydrodynamic transfection. However, we were unable to detect significant changes in liver iron levels upon reconstitution of these candidate genes. Taken together, our work provides strong genetic evidence of the existence of iron modifiers on Chr16. Moreover, we were able to delineate the phenotypically responsible region to a 0.8 Mb region containing 11 coding genes, 3 of which harbor missense mutations, using a series of congenic mice.

SUBMITTER: Guo X

PROVIDER: S-EPMC3651197 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Fine-mapping and genetic analysis of the loci affecting hepatic iron overload in mice.

Guo Xin X Zhang Zhuzhen Z Zhang Fan F Tao Yunlong Y An Peng P Wu Qian Q Wang Chia-Yu CY Knutson Mitchell D MD Wang Fudi F

PloS one 20130510 5

The liver, as the major organ for iron storage and production of hepcidin, plays pivotal roles in maintaining mammalian iron homeostasis. A previous study showed that Quantitative Trait Loci (QTLs) on chromosome 7 (Chr7) and 16 (Chr16) may control hepatic non-heme iron overload in an F2 intercross derived from C57BL/6J (B6) and SWR/J (SWR) mice. In this study, we aimed to validate the existence of these loci and identify the genes responsible for the phenotypic variations by generating congenic ...[more]

PMID: 23675470

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Project description:BackgroundR2*-MRI is clinically used to noninvasively assess hepatic iron content (HIC) to guide potential iron chelation therapy. However, coexisting pathologies, such as fibrosis and steatosis, affect R2* measurements and may thus confound HIC estimations.PurposeTo evaluate whether a multispectral auto regressive moving average (ARMA) model can be used in conjunction with quantitative susceptibility mapping (QSM) to measure magnetic susceptibility as a confounder-free predictor of HIC.Study typePhantom study and in vivo cohort.SubjectsNine iron phantoms covering clinically relevant R2* range (20-1200/second) and 48 patients (22 male, 26 female, median age 18 years).Field strength/sequenceThree-dimensional (3D) and two-dimensional (2D) multi-echo gradient echo (GRE) at 1.5 T.AssessmentARMA-QSM modeling was performed on the complex 3D GRE signal to estimate R2*, fat fraction (FF), and susceptibility measurements. R2*-based dry clinical HIC values were calculated from the 2D GRE acquisition using a published R2*-HIC calibration curve as reference standard.Statistical testsLinear regression analysis was performed to compare ARMA R2* and susceptibility-based estimates to iron concentrations and dry clinical HIC values in phantoms and patients, respectively.ResultsIn phantoms, the ARMA R2* and susceptibility values strongly correlated with iron concentrations (R2 ≥ 0.9). In patients, the ARMA R2* values highly correlated (R2 = 0.97) with clinical HIC values with slope = 0.026, and the susceptibility values showed good correlation (R2 = 0.82) with clinical dry HIC values with slope = 3.3 and produced a dry-to-wet HIC ratio of 4.8.Data conclusionThis study shows the feasibility that ARMA-QSM can simultaneously estimate susceptibility-based wet HIC, R2*-based dry HIC and FFs from a single multi-echo GRE acquisition. Our results demonstrate that both, R2* and susceptibility-based wet HIC values estimated with ARMA-QSM showed good association with clinical dry HIC values with slopes similar to published R2*-biopsy HIC calibration and dry-to-wet tissue weight ratio, respectively. Hence, our study shows that ARMA-QSM can provide potentially confounder-free assessment of hepatic iron overload.Level of evidence3 TECHNICAL EFFICACY: Stage 2.

Dataset Information

Fine-mapping and genetic analysis of the loci affecting hepatic iron overload in mice.

Publications

Fine-mapping and genetic analysis of the loci affecting hepatic iron overload in mice.

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