New mutations in the <i>SLC7A7</i> gene of two chinese sisters with lysinuric protein intolerance

Zhang, Guoqing; Cao, Ling

doi:10.1002/ppul.23760

Cited by 18 publications

(12 citation statements)

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“…Over 200 LPI patients have been reported worldwide, with isolated populations in Finland and Japan showing the highest prevalence (1:60,000 and 1:57,000, respectively) [5,6,7]. In addition, clusters of patients have been reported in southern Italy [8], North Africa [9] and Turkey [10,11] and sporadic cases in Greece, Pakistan [12], China [13] and Spain [1]. Although up to 50 mutations have been described [9], all the Finnish patients share the same point mutation, c.895-2A > T, which generates an acceptor splice site error that leads to a frameshift deletion and the loss of y + LAT1 activity [1,2].…”

Section: Introductionmentioning

confidence: 99%

Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease

Bodoy

Sotillo

Guarch

et al. 2019

IJMS

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Lysinuric protein intolerance (LPI) is a rare autosomal disease caused by defective cationic amino acid (CAA) transport due to mutations in SLC7A7, which encodes for the y+LAT1 transporter. LPI patients suffer from a wide variety of symptoms, which range from failure to thrive, hyperammonemia, and nephropathy to pulmonar alveolar proteinosis (PAP), a potentially life-threatening complication. Hyperammonemia is currently prevented by citrulline supplementation. However, the full impact of this treatment is not completely understood. In contrast, there is no defined therapy for the multiple reported complications of LPI, including PAP, for which bronchoalveolar lavages do not prevent progression of the disease. The lack of a viable LPI model prompted us to generate a tamoxifen-inducible Slc7a7 knockout mouse (Slc7a7−/−). The Slc7a7−/− model resembles the human LPI phenotype, including malabsorption and impaired reabsorption of CAA, hypoargininemia and hyperammonemia. Interestingly, the Slc7a7−/− mice also develops PAP and neurological impairment. We observed that citrulline treatment improves the metabolic derangement and survival. On the basis of our findings, the Slc7a7−/− model emerges as a promising tool to further study the complexity of LPI, including its immune-like complications, and to design evidence-based therapies to halt its progression.

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Section: Introductionmentioning

confidence: 99%

Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease

Bodoy

Sotillo

Guarch

et al. 2019

IJMS

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“…The heteromeric y + LAT1 transporter, composed of a light subunit (encoded by SLC7A7 ) and a heavy subunit (encoded by SLC3A2 ), catalyzes the transmembrane efflux of arginine, lysine and ornithine in certain epithelial and non-epithelial cell types ( Broer, 2008 ; Broer and Gauthier-Coles, 2022 ; Palacin et al, 2004 ). LPI is a severe multi-system disorder characterized by growth failure ( Awrich et al, 1975 ; Goto et al, 1984 ; Carpenter et al, 1985 ; Nagata et al, 1987 ; Takada et al, 1987 ; Parini et al, 1991 ; Svedstrom et al, 1993 ; Parenti et al, 1995 ; Parsons et al, 1996 ; Kamoda et al, 1998 ; Korman et al, 2002 ; Moosa et al, 2005 ; Esposito et al, 2006 ; Gomez et al, 2006 ; Ogier de Baulny et al, 2012 ; Ko et al, 2012 ; Guzel-Ozanturk et al, 2013 ; Posey et al, 2014 ; Evelina et al, 2015 ; Bijarnia-Mahay et al, 2016 ; Deogaonkar and Shah, 2016 ; Noguchi et al, 2016 ; Mauhin et al, 2017 ; Stanley et al, 2017 ; Zhang and Cao, 2017 ; Olgac et al, 2020 ; Kang et al, 2019 ; Aljishi et al, 2020 ; Contreras et al, 2021 ; Andrews et al, 2021 ; Al-Qattan et al, 2021 ; Hashmi and Ahmed, 2022 ; Lee et al, 2022 ; Alqarajeh et al, 2020 ; Nicolas et al, 2016 ), short stature ( Awrich et al, 1975 ; Goto et al, 1984 ; Carpenter et al, 1985 ; Nagata et al, 1987 ; Takada et al, 1987 ; Parini et al, 1991 ; Parenti et al, 1995 ; Parsons et al, 1996 ; Kamoda et al, 1998 …”

Section: Introductionmentioning

confidence: 99%

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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“…Due to the poor intestinal uptake and loss of amino acids in the urine, patients have decreased plasma levels and increased urinary levels of CAA. A high incidence of this disease has been found in Finland (1:60000) ( 1 , 2 ), Southern Italy ( 3 ), and Northern Japan ( 4 ), but cases have also been reported in Korea ( 5 ), Turkey ( 6 ), Malaysia ( 7 ), China ( 8 ), and Mexico ( 9 ).…”

Section: Introductionmentioning

confidence: 99%

Immune Dysregulation Mimicking Systemic Lupus Erythematosus in a Patient With Lysinuric Protein Intolerance: Case Report and Review of the Literature

et al. 2021

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Lysinuric protein intolerance (LPI) is an inborn error of metabolism caused by defective transport of cationic amino acids in epithelial cells of intestines, kidneys and other tissues as well as non-epithelial cells including macrophages. LPI is caused by biallelic, pathogenic variants in SLC7A7. The clinical phenotype of LPI includes failure to thrive and multi-system disease including hematologic, neurologic, pulmonary and renal manifestations. Individual presentations are extremely variable, often leading to misdiagnosis or delayed diagnosis. Here we describe a patient that clinically presented with immune dysregulation in the setting of early-onset systemic lupus erythematosus (SLE), including renal involvement, in whom an LPI diagnosis was suspected post-mortem based on exome sequencing analysis. A review of the literature was performed to provide an overview of the clinical spectrum and immune mechanisms involved in this disease. The precise mechanism by which ineffective amino acid transport triggers systemic inflammatory features is not yet understood. However, LPI should be considered in the differential diagnosis of early-onset SLE, particularly in the absence of response to immunosuppressive therapy.

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New mutations in the SLC7A7 gene of two chinese sisters with lysinuric protein intolerance

Cited by 18 publications

References 10 publications

Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease

Inducible Slc7a7 Knockout Mouse Model Recapitulates Lysinuric Protein Intolerance Disease

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

Immune Dysregulation Mimicking Systemic Lupus Erythematosus in a Patient With Lysinuric Protein Intolerance: Case Report and Review of the Literature

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