RESUMEN
BACKGROUND Familial hypomagnesemia with secondary hypocalcemia (HSH) is a rare autosomal recessive disorder (OMIM# 602014) caused by mutations in the gene encoding transient receptor potential melastatin 6 (TRPM6)) on chromosome 9q22, a channel involved in epithelial magnesium resorption. While a plethora of studies have delineated various clinical manifestations pertinent to this mutation, the literature is devoid of connections between TRPM6 mutations and bleeding diathesis, or sudden infant death syndrome (SIDS). This report presents a case of familial HSH associated with the novel homozygous TRPM6 gene variant c.5281C>G p. (Arg1761Gly) chr9: 77354845. CASE REPORT This report details a 26-day-old neonate, born full term with optimal Apgar scores, who experienced an abrupt emergence of apnea, cyanosis, bilateral nasal bleeding, and diminished alertness. Despite the neonate's initially unremarkable clinical birth indicators, a meticulous assessment unveiled a pronounced family history of SIDS, including a sibling previously diagnosed with hypomagnesemia. Laboratory examination of the infant demonstrated severe hypomagnesemia and hypocalcemia, conditions which were promptly ameliorated following intravenous administration of magnesium and calcium. Whole-exome sequencing identified a homozygous TRPM6 gene mutation c.5281C>G p. (Arg1761Gly) at chr9: 77354845. This gene is crucial for magnesium regulation. The mutation involves a cytosine-to-guanine shift, resulting in an arginine to glycine amino acid substitution at position 1761 of the TRPM6 protein. CONCLUSIONS This report has highlighted that infantile hypomagnesemia may be associated with symptoms and signs that can mimic infection, or it can present with seizures. Although familial HSH is a rare genetic disorder that can be identified by genetic testing, correction of hypomagnesemia is the most important and immediate clinical management strategy.
Asunto(s)
Hipocalcemia , Deficiencia de Magnesio , Deficiencia de Magnesio/congénito , Muerte Súbita del Lactante , Canales Catiónicos TRPM , Lactante , Recién Nacido , Humanos , Magnesio , Hipocalcemia/genética , Hipocalcemia/complicaciones , Hipocalcemia/diagnóstico , Deficiencia de Magnesio/complicaciones , Deficiencia de Magnesio/diagnóstico , Deficiencia de Magnesio/genética , Canales Catiónicos TRPM/genéticaRESUMEN
Las enfermedades renales que cursan con hipomagnesemia son un grupo complejo y variopinto de tubulopatías producidas por mutaciones en genes que codifican proteínas que se expresan en la rama gruesa ascendente del asa de Henle y en el túbulo contorneado distal. En el presente artículo revisamos la descripción inicial, la expresividad clínica y la etiología de cuatro de las primeras causas de tubulopatías hipomagnesémicas que se describieron: las enfermedades de Bartter tipo 3 y Gitelman, la hipomagnesemia con hipocalcemia secundaria autosómica recesiva y la hipomagnesemia familiar con hipercalciuria y nefrocalcinosis. A continuación, se describen los patrones bioquímicos básicos que se observan en las hipomagnesemias tubulares renales y las modalidades de transporte e interacción que concurren entre los transportadores implicados en la reabsorción de magnesio en el túbulo contorneado distal. Finalmente, se comunica la reciente descripción de una nueva tubulopatía hipomagnesémica, la hipomagnesemia con hipocalcemia secundaria tipo 2 causada por una reducción de la actividad del canal TRPM7 (AU)
Renal diseases associated with hypomagnesemia are a complex and diverse group of tubulopathies caused by mutations in genes encoding proteins that are expressed in the thick ascending limb of the loop of Henle and in the distal convoluted tubule. In this paper, we review the initial description, the clinical expressiveness and etiology of four of the first hypomagnesemic tubulopathies described: Type 3 Bartter and Gitelman diseases,Autosomal recessive hypomagnesemia with secondary hypocalcemia and Familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The basic biochemical patterns observed in renal tubular hypomagnesemias and the modalities of transport and interaction that occur between the transporters involved in the reabsorption of magnesium in the distal convoluted tubule are described below. Finally, the recent report of a new renal disease with hypomagnesemia, Type 2 hypomagnesemia with secondary hypocalcemia caused by reduced TRPM7 channel activity is described (AU)
Asunto(s)
Humanos , Deficiencia de Magnesio/genética , Asa de la Nefrona/metabolismo , Túbulos Renales Distales/metabolismoRESUMEN
Magnesium is essential for the functioning and release of parathyroid hormone. Therefore, its deficiency can present as functional hypoparathyroidism. This case report describes a rare inherited disorder called congenital hypomagnesaemia with secondary hypocalcaemia due to TRPM6 gene mutation. This disease clinically and biochemically mimics hypoparathyroidism. However, unlike hypoparathyroidism, it can be treated only by long-term oral magnesium supplements. The patient presented to us with recurrent hypocalcaemic convulsions. The laboratory picture in each admission was similar to that of hypoparathyroidism. However, the hypocalcaemia persisted, and it was noticed to be associated with persistent hypomagnesaemia. A defect in the tubular magnesium reabsorption was postulated and a genetic analysis of the patient was done, which revealed a TRPM6 mutation causing hypomagnesaemia by excessive renal excretion of magnesium. The child responded well to oral magnesium supplements and is currently developmentally appropriate for her age and thriving well.
Asunto(s)
Hipocalcemia , Hipoparatiroidismo , Deficiencia de Magnesio , Canales Catiónicos TRPM , Niño , Femenino , Humanos , Magnesio/uso terapéutico , Hipocalcemia/tratamiento farmacológico , Hipocalcemia/genética , Hipocalcemia/complicaciones , Hipoparatiroidismo/complicaciones , Hipoparatiroidismo/tratamiento farmacológico , Hipoparatiroidismo/genética , Mutación , Deficiencia de Magnesio/complicaciones , Deficiencia de Magnesio/genética , Canales Catiónicos TRPM/genéticaRESUMEN
Dietary magnesium deficiency increases osteoclastic bone resorption and decreases osteoblastic bone formation. Increased bone resorption due to dietary magnesium deficiency can be explained by increased expression of the receptor activator of nuclear factor kB ligand. However, the detailed mechanisms underlying decreased bone formation remain unclear. Thus, in the present study, to determine the mechanism underlying decreased bone formation induced by dietary magnesium deficiency, we investigated the effects of short-term dietary magnesium deficiency on the mRNA expression of genes related to bone formation in rats. Male Wistar rats were fed a control or magnesium-deficient diet for eight days. The mRNA expression level of Runx2, Sp7, Bglap, Alpl, Col1a1, Igf1, and Bmp2 in the femur was significantly lower in magnesium-deficient rats than in control rats. These results suggest that short-term dietary magnesium deficiency decreases the gene expression of insulin-like growth factor-1 and bone morphogenetic protein 2, which, in turn, decreases osteoblastic bone formation through the downregulation of osteoblastogenesis-related gene expression.
Asunto(s)
Resorción Ósea , Deficiencia de Magnesio , Ratas , Masculino , Animales , Deficiencia de Magnesio/genética , Deficiencia de Magnesio/metabolismo , Osteogénesis/genética , Magnesio/metabolismo , Ratas Wistar , Resorción Ósea/metabolismo , ARN MensajeroRESUMEN
Vascular endothelial cells have a critical role in the maintenance of cardiovascular function. Evidence suggests that endothelial function may be compromised under conditions of magnesium deficiency, which increases vulnerability to inflammation. Whole genome transcription analysis was used to explore the acute (24 h) effects of magnesium on human umbilical vascular endothelial cells (HUVEC) cultured in low (0.1 mM) or high (5 mM) concentrations. With low magnesium 2728 transcripts were differentially expressed compared to the 1 mM control cultures and 3030 were differentially expressed with high magnesium. 615 transcripts were differentially expressed under both conditions, of which only 34 showed a concentration-dependent response. Analysis indicated that cellular organisation and biogenesis and key cellular processes such as apoptosis were impacted by both low and high conditions. High magnesium also influenced protein binding functions, intracellular signal transduction, metabolic and catalytic processes. Both conditions impacted on stress-related processes, in particular the inflammatory response. Key mediators of calcium-dependent regulation of gene expression were responsive to both high and low magnesium conditions. The HUVEC transcriptome is highly sensitive to acute changes in the concentration of magnesium in culture medium. The findings of this study support the view that whilst inflammation is an important process that is responsive to magnesium, the function of the endothelium may be impacted by other magnesium-induced changes including maintenance of cellular integrity, receptor expression and metabolic functions. The high proportion of transcripts that did not show a concentration-dependent response suggests variation in magnesium may elicit indirect changes, possibly mediated by other ions.
Asunto(s)
Deficiencia de Magnesio , Magnesio , Células Cultivadas , Endotelio Vascular , Células Endoteliales de la Vena Umbilical Humana , Humanos , Inflamación/metabolismo , Magnesio/metabolismo , Magnesio/farmacología , Deficiencia de Magnesio/genética , Deficiencia de Magnesio/metabolismo , Transcriptoma , Venas UmbilicalesRESUMEN
Chronic Mg2+ deficiency is the underlying cause of a broad range of health dysfunctions. As 25% of body Mg2+ is located in the skeletal muscle, Mg2+ transport and homeostasis systems (MgTHs) in the muscle are critical for whole-body Mg2+ homeostasis. In the present study, we assessed whether Mg2+ deficiency alters muscle fiber characteristics and major pathways regulating muscle physiology. C57BL/6J mice received either a control, mildly, or severely Mg2+-deficient diet (0.1%; 0.01%; and 0.003% Mg2+ wt/wt, respectively) for 14 days. Mg2+ deficiency slightly decreased body weight gain and muscle Mg2+ concentrations but was not associated with detectable variations in gastrocnemius muscle weight, fiber morphometry, and capillarization. Nonetheless, muscles exhibited decreased expression of several MgTHs (MagT1, CNNM2, CNNM4, and TRPM6). Moreover, TaqMan low-density array (TLDA) analyses further revealed that, before the emergence of major muscle dysfunctions, even a mild Mg2+ deficiency was sufficient to alter the expression of genes critical for muscle physiology, including energy metabolism, muscle regeneration, proteostasis, mitochondrial dynamics, and excitation-contraction coupling.
Asunto(s)
Proteínas de Transporte de Catión/metabolismo , Homeostasis/genética , Deficiencia de Magnesio/genética , Magnesio/metabolismo , Músculo Esquelético/metabolismo , Animales , Modelos Animales de Enfermedad , Metabolismo Energético/genética , Ratones , Ratones Endogámicos C57BL , Fibras Musculares Esqueléticas/metabolismo , Transducción de Señal/genéticaRESUMEN
OBJECTIVES: Hypomagnesemia 1, intestinal (HOMG1) is characterized by neurological symptoms that occur due to hypocalcemia and hypomagnesemia and caused by mutations in the TRPM6. Most of the identified variants in TRPM6 lead to premature termination: nonsense, frameshift, deletion, and splice site mutations. CASE PRESENTATION: Herein, we report a 1.5 month-old case who presented with convulsion due to hypocalcemia and hypomagnesemia in the early infancy. Sequencing of TRPM6 revealed a novel homozygous synonymous variant [c.2538G > A (p.Thr846Thr)] in the last codon of exon 19, which is most likely to affect the splicing. We report a novel homozygous synonymous variant in the TRPM6 leading to HOMG1, expanding the mutational spectrum. CONCLUSIONS: Synonymous mutations that were previously considered as harmless should be evaluated at the nucleotide level, keeping in mind that they may affect splicing and cause to the disease.
Asunto(s)
Hipocalcemia/genética , Deficiencia de Magnesio/congénito , Mutación , Canales Catiónicos TRPM/genética , Femenino , Humanos , Lactante , Deficiencia de Magnesio/genéticaRESUMEN
BACKGROUND: Primary hypomagnesemia with secondary hypocalcemia (HSH) is a rare genetic disorder. Dysfunctional transient receptor potential melastatin 6 causes impaired intestinal absorption of magnesium, leading to low serum levels accompanied by hypocalcemia. Typical signs at initial manifestation are generalized seizures, tetany, and/or muscle spasms. CASE REPORT: We present a 5 w/o female manifesting tonic-clonic seizures. Laboratory tests detected severe hypomagnesemia and hypocalcemia. The molecular genetic analysis revealed two novel mutations within the TRPM6 gene c.3308dupC (p.Pro1104Thrfs*28) (p.P1104Tfs*28) and c.3958C>T (p.Gln1302*) (p.Q1302*) and the patient was successfully treated with Mg supplementation. CONCLUSION: Ion disbalance should be taken into account in the differential diagnosis of infantile seizures. Accurate diagnosis of HSH together with appropriate treatment are crucial to prevent irreversible neurological outcomes.
Asunto(s)
Hipocalcemia , Deficiencia de Magnesio , Canales Catiónicos TRPM , Femenino , Humanos , Hipercalciuria , Hipocalcemia/genética , Magnesio , Deficiencia de Magnesio/congénito , Deficiencia de Magnesio/genética , Mutación , Nefrocalcinosis , Defectos Congénitos del Transporte Tubular Renal , Convulsiones/genética , Canales Catiónicos TRPM/genéticaAsunto(s)
Infecciones por Virus de Epstein-Barr/patología , Linfoma Cutáneo de Células T/patología , Deficiencia de Magnesio/patología , Magnesio/metabolismo , Neoplasias Cutáneas/patología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/patología , Adolescente , Infecciones por Virus de Epstein-Barr/genética , Humanos , Linfoma Cutáneo de Células T/genética , Deficiencia de Magnesio/genética , Masculino , Neoplasias Cutáneas/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genéticaRESUMEN
Patients with mutations in Cyclin M2 (CNNM2) suffer from hypomagnesaemia, seizures, and intellectual disability. Although the molecular function of CNNM2 is under debate, the protein is considered essential for renal Mg2+ reabsorption. Here, we used a Cnnm2 knock out mouse model, generated by CRISPR/Cas9 technology, to assess the role of CNNM2 in Mg2+ homeostasis. Breeding Cnnm2+/- mice resulted in a Mendelian distribution at embryonic day 18. Nevertheless, only four Cnnm2-/- pups were born alive. The Cnnm2-/- pups had a significantly lower serum Mg2+ concentration compared to wildtype littermates. Subsequently, adult Cnnm2+/- mice were fed with low, control, or high Mg2+ diets for two weeks. Adult Cnnm2+/- mice showed mild hypomagnesaemia compared to Cnnm2+/+ mice and increased serum Ca2+ levels, independent of dietary Mg2+ intake. Faecal analysis displayed increased Mg2+ and Ca2+ excretion in the Cnnm2+/- mice. Transcriptional profiling of Trpm6, Trpm7, and Slc41a1 in kidneys and colon did not reveal effects based on genotype. Microcomputed tomography analysis of the femurs demonstrated equal bone morphology and density. In conclusion, CNNM2 is vital for embryonic development and Mg2+ homeostasis. Our data suggest a previously undescribed role of CNNM2 in the intestine, which may contribute to the Mg2+ deficiency in mice and patients.
Asunto(s)
Proteínas de Transporte de Catión/genética , Discapacidad Intelectual/genética , Deficiencia de Magnesio/genética , Animales , Animales Recién Nacidos , Embrión de Mamíferos , Femenino , Discapacidad Intelectual/sangre , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/patología , Magnesio/sangre , Deficiencia de Magnesio/sangre , Deficiencia de Magnesio/complicaciones , Deficiencia de Magnesio/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Embarazo , Convulsiones/sangre , Convulsiones/complicaciones , Convulsiones/genéticaRESUMEN
AIMS: Dietary Mg2+ deficiency (MgD) impairs hippocampus-dependent memory in mice; however, the molecular mechanisms underlying MgD-induced memory impairments are unclear. Here, we investigated the molecular signatures in the hippocampus of MgD mice by analyzing the hippocampal transcriptome. METHODS: We performed RNA-sequencing of the hippocampal transcriptome of MgD mice. We used gene ontology analyses and quantitative real-time PCR to validate the RNA-sequencing results. RESULTS: mRNAs for neuroinflammation-related genes were upregulated in the hippocampus and cortex of MgD mice. CONCLUSION: MgD induces neuroinflammation in the mouse brain, including the hippocampus and cortex. Our findings suggest that MgD-induced neuroinflammation triggers the impairments of hippocampus-dependent memory.
Asunto(s)
Deficiencia de Magnesio , Animales , Hipocampo , Deficiencia de Magnesio/complicaciones , Deficiencia de Magnesio/genética , Trastornos de la Memoria , Ratones , Ratones Endogámicos C57BL , Enfermedades NeuroinflamatoriasRESUMEN
Objective: Familial hypomagnesemia with secondary hypocalcemia (HSH) is an autosomal recessive disease caused by a mutation in the transient receptor potential melastatin 6 (TRPM6) gene and is characterized by selective magnesium malabsorption. Affected cases are usually diagnosed during infancy and usually present with seizures due to hypocalcemia and hypomagnesemia. Irreversible neurological deficits and arrhythmias can be observed without appropriate treatment. The aim was to evaluate the long-term follow-up of patients with genetically confirmed HSH. Methods: A total of six patients with HSH, two of whom were siblings, were included. Age at diagnosis, clinical, laboratory and follow-up data on admission were recorded. All 39 exons of the TRPM6 gene and flanking exon-intron junctions from genomic DNA were amplified and sequenced in all cases. Results: The median (range) follow-up duration was 12.1 (7.6-21.7) years. All cases were diagnosed in infancy. Four different mutations, three of which had not been previously reported, were detected in the TRPM6 gene. Treatment compliance was good and there were no severe complications in the long-term follow-up of cases. However, mental retardation, specific learning difficulty and attention deficit/hyperactive disorder were observed as comorbidities. Conclusion: Of the four different TRPM6 mutations in this small cohort, three had not been previously reported. The long-term prognosis of HSH appears to be good, given early diagnosis and good treatment compliance. This long-term follow-up and prognostic data and the three novel mutations will contribute to the published evidence concerning this rare condition, HSH, and it is hoped will prevent negative outcomes.
Asunto(s)
Hipocalcemia/genética , Deficiencia de Magnesio/congénito , Mutación , Canales Catiónicos TRPM , Adolescente , Factores de Edad , Niño , Desarrollo Infantil , Preescolar , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Hipocalcemia/diagnóstico , Hipocalcemia/tratamiento farmacológico , Hipocalcemia/metabolismo , Lactante , Compuestos de Magnesio/uso terapéutico , Deficiencia de Magnesio/diagnóstico , Deficiencia de Magnesio/tratamiento farmacológico , Deficiencia de Magnesio/genética , Deficiencia de Magnesio/metabolismo , Masculino , Fenotipo , Estudios Retrospectivos , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismo , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Hypomagnesemia is a rare cause of seizures in childhood but should be kept in mind in recurrent and intractable seizures and hypocalcemia in communities where consanguineous marriages are common. Familial hypomagnesemia with secondary hypocalcemia is a rare genetic cause of hypomagnesemia, due to variants in the transient receptor potential melastatin 6 (TRPM6) genes. Here, a three year-old boy with a novel variant in this gene and had difficulties with enteral hypomagnesemia treatment is presented. He had recurrent seizures since two years of age and was diagnosed with epilepsy and treated with multiple antiepileptic drugs. Subsequently, he was diagnosed with rickets due to severe hypocalcemia at another center. The patient was hypotonic and neurodevelopmentally poor. The most prominent laboratory finding was of hypomagnesemia with secondary hypocalcemia. The genetic analysis revealed a novel variant in the TRPM6 gene. After parental treatment of intravenous magnesium (Mg2+) sulfate and calcium, the treatment was switched to enteral Mg2+ medications, due to persistent hypomagnesemia and the gastrointestinal side-effects, different oral preparations were used. The patient was stable on an oral maintenance dose of Mg2+ oxide with borderline blood Mg2+ levels and resolution of hypocalcemia. Hypomagnesemia is one of the causes of hypocalcemia. Enteral replacement is the key treatment but the treatment should be individualized for each patient. Normalization of hypomagnesemia is not always easy and should not be the aim of the treatment.
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Hipocalcemia/tratamiento farmacológico , Deficiencia de Magnesio/tratamiento farmacológico , Deficiencia de Magnesio/genética , Óxido de Magnesio/farmacología , Canales Catiónicos TRPM/genética , Preescolar , Humanos , Hipocalcemia/etiología , Deficiencia de Magnesio/complicaciones , Óxido de Magnesio/administración & dosificación , MasculinoRESUMEN
BACKGROUND: Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubulopathy characterized by excessive urinary wasting of magnesium and calcium, bilateral nephrocalcinosis, and progressive chronic renal failure in childhood or adolescence. FHHNC is caused by mutations in CLDN16 and CLDN19, which encode the tight-junction proteins claudin-16 and claudin-19, respectively. Most of these mutations are missense mutations and large deletions are rare. METHODS: We examined the clinical and biochemical features of a Spanish boy with early onset of FHHNC symptoms. Exons and flanking intronic segments of CLDN16 and CLDN19 were analyzed by direct sequencing. We developed a new assay based on Quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF) to investigate large CLDN16 deletions. RESULTS: Genetic analysis revealed two novel compound heterozygous mutations of CLDN16, comprising a missense mutation, c.277G>A; p.(Ala93Thr), in one allele, and a gross deletion that lacked exons 4 and 5,c.(840+25_?)del, in the other allele. The patient inherited these variants from his mother and father, respectively. CONCLUSIONS: Using direct sequencing and our QMPSF assay, we identified the genetic cause of FHHNC in our patient. This QMPSF assay should facilitate the genetic diagnosis of FHHNC. Our study provided additional data on the genotypic spectrum of the CLDN16 gene.
Asunto(s)
Claudinas/genética , Eliminación de Gen , Deficiencia de Magnesio/genética , Mutación Missense , Nefrocalcinosis/genética , Heterocigoto , Humanos , Lactante , Deficiencia de Magnesio/patología , Masculino , Nefrocalcinosis/patología , FenotipoRESUMEN
Claudins are integral proteins expressed at the tight junctions of epithelial and endothelial cells. In the mammalian kidney, every tubular segment express a specific set of claudins that give to that segment unique properties regarding permeability and selectivity of the paracellular pathway. So far, 3 claudins (10b, 16 and 19) have been causally traced to rare human syndromes: variants of CLDN10b cause HELIX syndrome and variants of CLDN16 or CLDN19 cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis. The review summarizes our current knowledge on the physiology of mammalian tight junctions and paracellular ion transport, as well as on the role of the 3 above-mentioned claudins in health and disease. Claudin 14, although not having been causally linked to any rare renal disease, is also considered, because available evidence suggests that it may interact with claudin 16. Some single-nucleotide polymorphisms of CLDN14 are associated with urinary calcium excretion and/or kidney stones. For each claudin considered, the pattern of expression, the function and the human syndrome caused by pathogenic variants are described.
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Claudinas/metabolismo , Túbulos Renales/metabolismo , Deficiencia de Magnesio/genética , Nefrocalcinosis/genética , Animales , Claudinas/genética , Humanos , Transporte Iónico , Deficiencia de Magnesio/metabolismo , Nefrocalcinosis/metabolismo , Uniones Estrechas/metabolismoRESUMEN
X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia (XMEN) disease are caused by deficiency of the magnesium transporter 1 (MAGT1) gene. We studied 23 patients with XMEN, 8 of whom were EBV naive. We observed lymphadenopathy (LAD), cytopenias, liver disease, cavum septum pellucidum (CSP), and increased CD4-CD8-B220-TCRαß+ T cells (αßDNTs), in addition to the previously described features of an inverted CD4/CD8 ratio, CD4+ T lymphocytopenia, increased B cells, dysgammaglobulinemia, and decreased expression of the natural killer group 2, member D (NKG2D) receptor. EBV-associated B cell malignancies occurred frequently in EBV-infected patients. We studied patients with XMEN and patients with autoimmune lymphoproliferative syndrome (ALPS) by deep immunophenotyping (32 immune markers) using time-of-flight mass cytometry (CyTOF). Our analysis revealed that the abundance of 2 populations of naive B cells (CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4++CD10+CD38+ and CD20+CD27-CD22+IgM+HLA-DR+CXCR5+CXCR4+CD10-CD38-) could differentially classify XMEN, ALPS, and healthy individuals. We also performed glycoproteomics analysis on T lymphocytes and show that XMEN disease is a congenital disorder of glycosylation that affects a restricted subset of glycoproteins. Transfection of MAGT1 mRNA enabled us to rescue proteins with defective glycosylation. Together, these data provide new clinical and pathophysiological foundations with important ramifications for the diagnosis and treatment of XMEN disease.
Asunto(s)
Síndrome Linfoproliferativo Autoinmune/inmunología , Deficiencia de Magnesio/inmunología , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/inmunología , Antígenos CD/genética , Antígenos CD/inmunología , Síndrome Linfoproliferativo Autoinmune/genética , Síndrome Linfoproliferativo Autoinmune/patología , Relación CD4-CD8 , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/inmunología , Femenino , Glicosilación , Humanos , Deficiencia de Magnesio/genética , Deficiencia de Magnesio/patología , Masculino , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/genética , Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X/patologíaRESUMEN
Se presenta el caso de una niña de diez años diagnosticada de nefrocalcinosis bilateral tras un estudio radiológico solicitado por sospecha de escoliosis. El estudio de sangre y orina inicial nos orienta hacia el diagnóstico de una rara enfermedad, como es el síndrome de hipomagnesemia familiar con hipercalciuria y nefrocalcinosis. El diagnóstico genético dirigido solicitado en ámbito hospitalario confirma el diagnóstico y permite iniciar el tratamiento
We present the case of a ten-year-old girl diagnosed with bilateral nephrocalcinosis after a radiological study requested for suspected scoliosis. The initial blood test and urine test guided us to the diagnosis of the rare disease called familial hypomagnesemia syndrome with hypercalciuria and nephrocalcinosis. The genetic diagnosis requested in the hospital confirms the diagnosis and allows to start the treatment
Asunto(s)
Humanos , Femenino , Niño , Nefrocalcinosis/genética , Escoliosis/diagnóstico por imagen , Dolor de la Región Lumbar/diagnóstico por imagen , Deficiencia de Magnesio/genética , Hipercalciuria/genética , Hallazgos Incidentales , Dolor de la Región Lumbar/etiología , Diagnóstico DiferencialRESUMEN
OBJECTIVE: To explore the molecular pathogenesis for a pedigree affected with hypocalcemia secondary to hypomagnesemia. METHODS: Sanger sequencing was used to detect potential variant of the TRPM6 gene in the patient and their parents. RESULTS: The results showed that the patient has carried novel homozygous c.3311C>T (p.Pro1104Leu) variant of the TRMP6 gene, for which both of his parents were heterozygous carriers. Analysis of protein functions using software predicted high risk of pathogenicity. CONCLUSION: The homozygous c.3311C>T (p.Pro1104Leu) variant of the TRPM6 gene probably underlies the disease in this patient.
Asunto(s)
Hipocalcemia/genética , Deficiencia de Magnesio/genética , Canales Catiónicos TRPM/genética , Heterocigoto , Humanos , Magnesio , Masculino , LinajeRESUMEN
OBJECTIVE: To explore the clinical features and mutations of the TRPM6 gene in an infant featuring hypomagnesemia and secondary hypocalcemia. METHODS: Clinical data of the patient was collected. Genomic DNA was extracted from peripheral blood samples from the patient and her parents. Targeted exome sequencing was carried out to screen the potential mutations. Suspected mutations were verified by Sanger sequencing. RESULTS: A novel homozygous c.5538delA (p.Q1846Qfs*2) mutation in the TRPM6 gene was identified in the proband, for which both of her parents were heterozygous carriers. CONCLUSION: The homozygous frameshift mutation of TRPM6 gene (c.5538delA) probably underlies the disease in the proband. The finding has expanded the mutation spectrum of TRPM6 gene.