Lysinuric protein intolerance mimicking N-acetylglutamate synthase deficiency in a nine-year-old boy

Al-Qattan, Sarah; Malcolmson, Caroline; Mercimek‐Andrews, Saadet

doi:10.1016/j.ymgmr.2021.100741

Cited by 3 publications

(13 citation statements)

References 23 publications

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“…Moreover, the L-arginine catalytic enzyme endothelial nitric oxide synthase (eNOS) can be found in erythrocytes, where parasite-arginine deprivation decreases deformability of these cells as a result of reduced NO production (Cobbold et al, 2016). Here we show that upon ablation of Slc7a7 in all cells, erythrocytes present reduced mean corpuscular volume and mean corpuscular hemoglobine, which has also been also described in LPI patients (Al-Qattan et al, 2021). Since arginine is the metabolite recovered by citrulline administration, we hypothesized that hypoargininemia plays a key role in erythropoiesis and RBC size.…”

Section: Discussionsupporting

confidence: 79%

“…Substantial advances in the research field of LPI have been scarce during the last decade, which can be probably explained by the huge phenotypic variability found among LPI patients (Al-Qattan et al, 2021; Ogier de Baulny et al, 2012; Posey et al, 2014). In a previous work we showed that the inducible total Slc7a7 -/- mouse model recapitulates the main hallmarks of the human LPI complications, such as hypoargininemia, hyperammonemia and PAP (Bodoy et al, 2019; Ogier de Baulny et al, 2012; Parto et al, 1994).…”

Section: Discussionmentioning

confidence: 99%

“…Moreover, the systemic metabolic condition of LPI is an essential driver for the hematologic complications. In addition, Slc7a7 -/- mice showed deficient erythropoyesis, a trait that paralels the reduced number of reticulocytes in some LPI patients, an alteration that has not been fully explored (Al-Qattan et al, 2021). Our results shifted the spotlight of increased erythrophagocytosis by abnormally functioning macrophages to altered erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

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DefectiveSlc7a7transport reduces erythropoietin compromising erythropoiesis and iron homeostasis

Sotillo

Giroud-Gerbetant

Couso

et al. 2021

Preprint

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Slc7a7 encodes for y+LAT1, a transporter of cationic amino acid across the basolateral membrane of epithelial cells. Mutations in SLC7A7 gene give rise to Lysinuric Protein Intolerance (LPI), a rare autosomal recessive disease with wide variability of complications. Intriguingly, y+LAT1 is also involved in arginine transport in non polarized cells such as macrophages. Here we report that complete inducible Slc7a7 ablation in mouse compromises systemic arginine availability that alters proper erythropoiesis and that dysfunctional RBC generation leads to increased erythrophagocytosis, iron overload and an altered iron metabolism by macrophages. Herein, uncovering a novel mechanism that links amino acid metabolism to erythropoiesis and iron metabolism. Mechanistically, the iron exporter ferroportin-1 expression was compromised by increased plasma hepcidin causing macrophage iron accumulation. Strikingly, lysozyme M-cell-specific knockout mice failed to reproduce the total knockout alterations, while bone marrow transplantation experiments resulted in the resolution of macrophage iron overload but could not overcome erythropoietic defect. This study establishes a new crucial link between systemic arginine availability in erythropoiesis and iron homeostasis.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

DefectiveSlc7a7transport reduces erythropoietin compromising erythropoiesis and iron homeostasis

Sotillo

Giroud-Gerbetant

Couso

et al. 2021

Preprint

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“…In fact, LPI has been reported in several cases of HLH complications. [45][46][47][48][49][50][51][52][53] Furthermore, some patients developed HLH prior to being diagnosed with LPI (Table 3). Notably, most patients with HLH have reversible laboratory abnormalities that normalize with remission, whereas LPI-associated HLH is chronic and intermittent.…”

Section: Lysinuric Protein Intolerancementioning

confidence: 99%

“…45,47 Hyperthermia may not be present in LPIassociated HLH. 45,50,51,53 Several cases of bone marrow abnormalities have also been reported, though they were not diagnosed with HLH. 54,55 The majority of patients with LPI-associated HLH resolve spontaneously or with LPI therapeutic intervention.…”

Section: Lysinuric Protein Intolerancementioning

confidence: 99%

Rare diseases presenting with hemophagocytic lymphohistiocytosis

Kanegane

Noguchi

Yamada

et al. 2023

Pediatrics International

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Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyperinflammatory disorder characterized by hypercytokinemia caused by excessive activation of cytotoxic T cells and macrophages. HLH is caused by a variety of factors and is classified into primary and secondary HLH. Familial HLH (FHL) types 1–5, X‐linked lymphoproliferative syndrome types 1 and 2, and FHL syndrome with hypopigmentation are all examples of primary HLH. Secondary HLH, on the other hand, is linked to infections, malignant tumors, autoimmune diseases, and other diseases. The causes of HLH vary, and finding the underlying disease is critical for diagnosis and treatment. The majority of HLH is caused by the aforementioned conditions; however, approximately 10% of cases are caused by rare diseases such as inborn errors of immunity (IEI) and inborn errors of metabolism (IEM). Novel IEI, such as RhoG, MAP kinase activating death domain, TIM3, and ZNFX1 deficiencies, have recently been identified as causes of HLH. IEM patients are rarely associated with HLH. Surprisingly, children with lysinuric protein intolerance and lysosomal acid lipase deficiency (Wolman disease) frequently develop HLH. This review focuses on the most recent knowledge of HLH caused by rare diseases such as IEI and IEM.

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Delayed skeletal development and IGF-1 deficiency in a mouse model of lysinuric protein intolerance

Stroup,

Li,

et al. 2023

Disease Models &Amp; Mechanisms

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SLC7A7 deficiency, or lysinuric protein intolerance (LPI), causes loss of function of the y+LAT1 transporter critical for efflux of arginine, lysine and ornithine in certain cells. LPI is characterized by urea cycle dysfunction, renal disease, immune dysregulation, growth failure, delayed bone age, and osteoporosis. We previously reported that Slc7a7 knockout mice (C57BL/6 x 129/SvEv F2) recapitulate LPI phenotypes, including growth failure. Our main objective was to characterize the skeletal phenotype in these mice. Compared to wild type littermates, juvenile Slc7a7 knockout mice demonstrated 70% lower body weights, 87% lower plasma IGF-1 concentrations, and delayed skeletal development. Because poor survival prevents evaluation of mature knockout mice, we generated a conditional Slc7a7 deletion in mature osteoblasts or mesenchymal cells of the osteo-chondroprogenitor lineage, butno differences in bone architecture were observed. Overall, global Slc7a7 deficiency caused growth failure with low plasma IGF-1 concentrations and delayed skeletal development, but Slc7a7 deficiency in the osteoblastic lineage was not a major contributor to these phenotypes. Future studies utilizing additional tissue-specific Slc7a7 knockout models may help dissect cell autonomous and non-cell autonomous mechanisms underlying phenotypes in LPI.

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Lysinuric protein intolerance mimicking N-acetylglutamate synthase deficiency in a nine-year-old boy

Cited by 3 publications

References 23 publications

DefectiveSlc7a7transport reduces erythropoietin compromising erythropoiesis and iron homeostasis

DefectiveSlc7a7transport reduces erythropoietin compromising erythropoiesis and iron homeostasis

Rare diseases presenting with hemophagocytic lymphohistiocytosis

Delayed skeletal development and IGF-1 deficiency in a mouse model of lysinuric protein intolerance

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