Nephrocalcinosis (enamel renal syndrome) caused by autosomal recessive FAM20A mutations

Calcium homeostasis requires regulated cellular and interstitial systems interacting to modulate the activity and movement of this ion. Disruption of these systems in the kidney results in nephrocalcinosis and nephrolithiasis, important medical problems whose pathogenesis is incompletely understood

Representaciones sociales sobre lactancia materna y alimentación complementaria en familias que se atienden en un hospital público de la provincia de Buenos Aires

Introducción: La lactancia materna y una alimentación complementaria adecuada en los primeros dos años del niño son fundamentales para lograr un mejor crecimiento y desarrollo, estando dichas prácticas moldeadas por las representaciones sociales de cada familia. El objetivo de este trabajo fue conocer las representaciones sociales sobre lactancia materna, la alimentación complementaria y sobre el sistema de salud en relación a las prácticas de alimentación de familias que realizaron el control de salud de sus niños en un hospital público de la Provincia de Buenos Aires. Metodología: Se utilizó un diseño cualitativo, a través de dos grupos focales con familiares responsables de la alimentación de niños que realizaban sus controles en los consultorios pediátricos del Observatorio de salud del IDIP durante los meses noviembre 2022 a marzo 2023. A partir del análisis se llegó a la construcción de distintas subcategorías de representaciones sociales: valores, creencias, aprendizajes, normas y mitos. El proyecto fue aprobado por el Comité de Ética Institucional. Resultados: Se encontró una valoración de la lactancia materna como práctica que refuerza el vínculo con el lactante y como el mejor alimento para el niño. Los factores socioeconómicos y el tiempo se identificaron como limitantes para lograr una alimentación complementaria saludable. El sistema de salud se presentó como un constante generador de información sobre las formas de inicio y mantenimiento de estas prácticas. Conclusiones: Es fundamental conocer las representaciones sociales que moldean las prácticas de lactancia materna y alimentación complementaria de cada comunidad para diseñar acciones desde el sistema de salud enfocadas en la prevención de la malnutrición infantil, y en consecuencia, las enfermedades crónicas no transmisibles, promoviendo una nutrición sana y un óptimo desarrollo físico y mental. mejor alimento para el niño. Los factores socioeconómicos y el tiempo se identificaron como limitantes para lograr una alimentación complementaria saludable.Introduction: Breastfeeding and adequate complementary feeding in the first two years of the child are essential to achieve better growth and development, these practices being shaped by the social representations of each family. We sought to know the social representations about breastfeeding and complementary feeding in families that carried out the health control of their children in a public hospital in the Province of Buenos Aires. Methodology: A qualitative design was used, through two focus groups with relatives responsible for feeding children who carried out their controls in the pediatric clinics of the IDIP Health Observatory during the months of November 2022 to March 2023. From the analysis, the construction of different subcategories of social representations was reached: values, beliefs, learning, norms and myths. The project was approved by the institutional ethics committee. Results: An assessment of breastfeeding was found as a practice that reinforces the bond with the infant and as the best food for the child. Socioeconomic factors and time were identified as limiting to achieve a healthy complementary diet. The health system was presented as a constant generator of information on the ways to start and maintain these feeding practices. Conclusions: It is essential to know the social representations that shape the practices of breastfeeding and complementary feeding in each community, to design actions from the health system focused on the prevention of child malnutrition, and consequently, chronic non-communicable diseases, promoting a healthy nutrition and optimal physical and mental development

Mistargeting of peroxisomal EHHADH and inherited renal Fanconi's syndrome

BACKGROUND In renal Fanconi's syndrome, dysfunction in proximal tubular cells leads to renal losses of water, electrolytes, and low-molecular-weight nutrients. For most types of isolated Fanconi's syndrome, the genetic cause and underlying defect remain unknown. METHODS We clinically and genetically characterized members of a five-generation black family with isolated autosomal dominant Fanconi's syndrome. We performed genomewide linkage analysis, gene sequencing, biochemical and cell-biologic investigations of renal proximal tubular cells, studies in knockout mice, and functional evaluations of mitochondria. Urine was studied with the use of proton nuclear magnetic resonance (1H-NMR) spectroscopy. RESULTS We linked the phenotype of this family's Fanconi's syndrome to a single locus on chromosome 3q27, where a heterozygous missense mutation in EHHADH segregated with the disease. The p.E3K mutation created a new mitochondrial targeting motif in the N-terminal portion of EHHADH, an enzyme that is involved in peroxisomal oxidation of fatty acids and is expressed in the proximal tubule. Immunocytofluorescence studies showed mistargeting of the mutant EHHADH to mitochondria. Studies of proximal tubular cells revealed impaired mitochondrial oxidative phosphorylation and defects in the transport of fluids and a glucose analogue across the epithelium. 1H-NMR spectroscopy showed elevated levels of mitochondrial metabolites in urine from affected family members. Ehhadh knockout mice showed no abnormalities in renal tubular cells, a finding that indicates a dominant negative nature of the mutation rather than haploinsufficiency. CONCLUSIONS Mistargeting of peroxisomal EHHADH disrupts mitochondrial metabolism and leads to renal Fanconi's syndrome; this indicates a central role of mitochondria in proximal tubular function. The dominant negative effect of the mistargeted protein adds to the spectrum of monogenic mechanisms of Fanconi's syndrome. (Funded by the European Commission Seventh Framework Programme and others.

A Founder Mutation in EHD1 Presents with Tubular Proteinuria and Deafness

Background The endocytic reabsorption of proteins in the proximal tubule requires a complex machinery and defects can lead to tubular proteinuria. The precise mechanisms of endocytosis and processing of receptors and cargo are incompletely understood. EHD1 belongs to a family of proteins presumably involved in the scission of intracellular vesicles and in ciliogenesis. However, the relevance of EHD1 in human tissues, in particular in the kidney, was unknown. Methods Genetic techniques were used in patients with tubular proteinuria and deafness to identify the disease-causing gene. Diagnostic and functional studies were performed in patients and disease models to investigate the pathophysiology. Results We identified six individuals (5–33 years) with proteinuria and a high-frequency hearing deficit associated with the homozygous missense variant c.1192C>T (p.R398W) in EHD1. Proteinuria (0.7–2.1 g/d) consisted predominantly of low molecular weight proteins, reflecting impaired renal proximal tubular endocytosis of filtered proteins. Ehd1 knockout and Ehd1R398W/R398W knockin mice also showed a high-frequency hearing deficit and impaired receptor-mediated endocytosis in proximal tubules, and a zebrafish model showed impaired ability to reabsorb low molecular weight dextran. Interestingly, ciliogenesis appeared unaffected in patients and mouse models. In silico structural analysis predicted a destabilizing effect of the R398W variant and possible inference with nucleotide binding leading to impaired EHD1 oligomerization and membrane remodeling ability. Conclusions A homozygous missense variant of EHD1 causes a previously unrecognized autosomal recessive disorder characterized by sensorineural deafness and tubular proteinuria. Recessive EHD1 variants should be considered in individuals with hearing impairment, especially if tubular proteinuria is noted

Glycine Amidinotransferase (GATM), Renal Fanconi Syndrome, and Kidney Failure

Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure. Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations. Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATMaggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death. Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis