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IRIDA Phenotype in TMPRSS6 Monoallelic-Affected Patients: Toward a Better Understanding of the Pathophysiology.

ABSTRACT: Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive inherited form of iron deficiency anemia characterized by discrepantly high hepcidin levels relative to body iron status. However, patients with monoallelic exonic TMPRSS6 variants have also been reported to express the IRIDA phenotype. The pathogenesis of an IRIDA phenotype in these patients is unknown and causes diagnostic uncertainty. Therefore, we retrospectively summarized the data of 16 patients (4 men, 12 women) who expressed the IRIDA phenotype in the presence of only a monoallelic TMPRSS6 variant. Eight unaffected relatives with identical exonic TMPRSS6 variants were used as controls. Haplotype analysis was performed to assess the (intra)genetic differences between patients and relatives. The expression and severity of the IRIDA phenotype were highly variable. Compared with their relatives, patients showed lower Hb, MCV, and TSAT/hepcidin ratios and inherited a different wild-type allele. We conclude that IRIDA in monoallelic TMPRSS6-affected patients is a phenotypically and genotypically heterogeneous disease that is more common in female patients. We hypothesize that allelic imbalance, polygenetic inheritance, or modulating environmental factors and their complex interplay are possible causes. This explorative study is the first step toward improved insights into the pathophysiology and improved diagnostic accuracy for patients presenting with IRIDA and a monoallelic exonic TMPRSS6 variant.

SUBMITTER: Hoving V

PROVIDER: S-EPMC9331965 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Histopathology of Anterior Urethral Strictures: Toward a Better Understanding of Stricture Pathophysiology.

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Mutations in TMPRSS6 cause iron-refractory iron deficiency anemia (IRIDA).

Project description:Iron deficiency is usually attributed to chronic blood loss or inadequate dietary intake. Here, we show that iron deficiency anemia refractory to oral iron therapy can be caused by germline mutations in TMPRSS6, which encodes a type II transmembrane serine protease produced by the liver that regulates the expression of the systemic iron regulatory hormone hepcidin. These findings demonstrate that TMPRSS6 is essential for normal systemic iron homeostasis in humans.

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A novel TMPRSS6 mutation that prevents protease auto-activation causes IRIDA.

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Toward a Better Understanding of Potential Roles of Astrocytes in HIV-1-associated Neurocognitive Disorders

2009-08-05 | GSE17383 | GEO

Toward a Better Understanding of Potential Roles of Astrocytes in HIV-1-associated Neurocognitive Disorders

Project description:We present a microarray analysis of primary mouse astrocytes exposed to HIV-1 in culture. Results are compared with previous genomic studies of HIV-1 effect in human astrocytes and human and macaque brains. Day-two neonatal mouse astrocytes were exposed in triplicates to cell-free HIV-1/NL4-3 at m.o.i. of 1 and cultured for 24 hours. As control, cells were treated in triplicates with a mock virus concentrate at the same dilution (vol/vol) as the wild-type virus. As an example of large scale gene expression analysis we shall provide some details of the method; full description is in Kim et al. (S.-Y. Kim et al., 2004). Total RNA was prepared from cell cultures using the RNAeasy total RNA extraction kit (Qiagen, CA). RNA quality was assessed by electrophoresis and spectrophotometric analysis; between 1 and 10 µg of total RNA was used to generate a cDNA, and then 1 µg of cDNA product was used in an in vitro transcription reaction that contained biotinylated UTP and CTP. Twenty µg of full-length cRNA was fragmented and was subjected to gene expression analysis on the Affymetrix Mouse Genome 430 2.0 Array chip. Affymetrix software was used to generate CHP files. Significance analysis was performed using ArrayAssist software (Stratagene).

2009-08-05 | E-GEOD-17383 | biostudies-arrayexpress

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Toward better understanding of artifacts in variant calling from high-coverage samples.

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