scholarly journals Clinical Heterogeneity and Phenotypic Expansion of NaPi-IIa–Associated Disease

2017 ◽  
Vol 102 (12) ◽  
pp. 4604-4614 ◽  
Author(s):  
Korcan Demir ◽  
Melek Yıldız ◽  
Hilla Bahat ◽  
Michael Goldman ◽  
Nisreen Hassan ◽  
...  
Keyword(s):  
Fanconi Syndrome ◽  
Loss Of Function ◽  
Renal Fanconi Syndrome ◽  
Whole Exome ◽  
Proximal Tubular ◽  
History Of ◽  
Proximal Tubulopathy ◽  
Idiopathic Infantile Hypercalcemia ◽  
Close Relatives

Abstract Context NaPi-IIa, encoded by SLC34A1, is a key phosphate transporter in the mammalian proximal tubule and plays a cardinal role in renal phosphate handling. NaPi-IIa impairment has been linked to various overlapping clinical syndromes, including hypophosphatemic nephrolithiasis with osteoporosis, renal Fanconi syndrome with chronic kidney disease, and, most recently, idiopathic infantile hypercalcemia and nephrocalcinosis. Objectives We studied the molecular basis of idiopathic infantile hypercalcemia with partial proximal tubulopathy in two apparently unrelated patients of Israeli and Turkish descent. Design Genetic analysis in two affected children and their close relatives was performed using whole-exome sequencing, followed by in vitro localization and trafficking analysis of mutant NaPi-IIa. Results Mutation and haplotype analyses in both patients revealed a previously described homozygous loss-of-function inserted duplication (p.I154_V160dup) in NaPi-IIa, which is inherited identical-by-descent from a common ancestor. The shared mutation was originally reported by our team in two adult siblings with renal Fanconi syndrome, hypophosphatemic bone disease, and progressive renal failure who are family members of one of the infants reported herein. In vitro localization assays and biochemical analysis of p.I154_V160dup and of additional NaPi-IIa mutants harboring a trafficking defect indicate aberrant retention at the endoplasmic reticulum in an immature and underglycosylated state, leading to premature proteasomal degradation. Conclusions Our findings expand the phenotypic spectrum of NaPi-IIa disruption, reinforce its link with proximal tubular impairment, enable longitudinal study of the natural history of the disease, and shed light on cellular pathways associated with loss of function and impaired trafficking of NaPi-IIa mutants.

scholarly journals Neither a Novel Tau Proteinopathy nor an Expansion of a Phenotype: Reappraising Clinicopathology-Based Nosology

2021 ◽  
Vol 22 (14) ◽  
pp. 7292
Author(s):  
Luca Marsili ◽  
Jennifer Sharma ◽  
Alberto J. Espay ◽  
Alice Migazzi ◽  
Elhusseini Abdelghany ◽  
...  
Keyword(s):  
Spinocerebellar Ataxia Type ◽  
Niemann Pick Disease ◽  
Whole Exome ◽  
Heterozygous Variant ◽  
History Of ◽  
Ataxia Syndrome ◽  
Niemann Pick

The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann–Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new heterozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.

Approach to the patient with renal Fanconi syndrome, glycosuria, or aminoaciduria

2018 ◽  
Author(s):  
Detlef Bockenhauer ◽  
Robert Kleta
Keyword(s):  
Fanconi Syndrome ◽  
Tubular Dysfunction ◽  
Renal Fanconi Syndrome ◽  
Renal Glycosuria ◽  
Proximal Tubular Dysfunction ◽  
Wide Range ◽  
Proximal Tubular ◽  
Proximal Tubular Function ◽  
Low Molecular Weight Proteins ◽  
Filtration Capacity

Up to 80% of filtered salt and water is returned back into the circulation in the proximal tubule. Several solutes, such as phosphate, glucose, low-molecular weight proteins, and amino acids are exclusively reabsorbed in this segment, so their appearance in urine is a sign of proximal tubular dysfunction. An entire orchestra of specialized apical and basolateral transporters, as well as paracellular molecules, mediate this reabsorption. Defects in proximal tubular function can be isolated (e.g. isolated renal glycosuria, aminoacidurias, or hypophosphataemic rickets) or generalized. In the latter case it is called the Fanconi–Debre–de Toni syndrome, based on the initial clinical descriptions. However, in clinical practice it is usually referred to as just the ‘renal Fanconi syndrome’. Severity of proximal tubular dysfunction can vary, and may coexist with some degree of loss of glomerular filtration capacity. Causes include a wide range of insults to proximal tubular cells, including a number of genetic conditions, drugs and poisons.

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

2018 ◽  
Vol 29 (7) ◽  
pp. 1849-1858 ◽  
Author(s):  
Markus Reichold ◽  
Enriko D. Klootwijk ◽  
Joerg Reinders ◽  
Edgar A. Otto ◽  
Mario Milani ◽  
...  
Keyword(s):  
Kidney Failure ◽  
Fanconi Syndrome ◽  
Genetic Disorder ◽  
Subsequent Development ◽  
Mitochondrial Morphology ◽  
Missense Mutations ◽  
Renal Fanconi Syndrome ◽  
Biopsy Specimens ◽  
Proximal Tubular ◽  
Renal Proximal Tubular

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. GATM aggregates-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.

scholarly journals TBC1D8B Mutations Implicate RAB11-Dependent Vesicular Trafficking in the Pathogenesis of Nephrotic Syndrome

2019 ◽  
Vol 30 (12) ◽  
pp. 2338-2353 ◽  
Author(s):  
Lina L. Kampf ◽  
Ronen Schneider ◽  
Lea Gerstner ◽  
Roland Thünauer ◽  
Mengmeng Chen ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Slit Diaphragm ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Steroid Resistant ◽  
Steroid Resistant Nephrotic Syndrome ◽  
Whole Exome ◽  
Immortalized Cell

BackgroundMutations in about 50 genes have been identified as monogenic causes of nephrotic syndrome, a frequent cause of CKD. These genes delineated the pathogenetic pathways and rendered significant insight into podocyte biology.MethodsWe used whole-exome sequencing to identify novel monogenic causes of steroid-resistant nephrotic syndrome (SRNS). We analyzed the functional significance of an SRNS-associated gene in vitro and in podocyte-like Drosophila nephrocytes.ResultsWe identified hemizygous missense mutations in the gene TBC1D8B in five families with nephrotic syndrome. Coimmunoprecipitation assays indicated interactions between TBC1D8B and active forms of RAB11. Silencing TBC1D8B in HEK293T cells increased basal autophagy and exocytosis, two cellular functions that are independently regulated by RAB11. This suggests that TBC1D8B plays a regulatory role by inhibiting endogenous RAB11. Coimmunoprecipitation assays showed TBC1D8B also interacts with the slit diaphragm protein nephrin, and colocalizes with it in immortalized cell lines. Overexpressed murine Tbc1d8b with patient-derived mutations had lower affinity for endogenous RAB11 and nephrin compared with wild-type Tbc1d8b protein. Knockdown of Tbc1d8b in Drosophila impaired function of the podocyte-like nephrocytes, and caused mistrafficking of Sns, the Drosophila ortholog of nephrin. Expression of Rab11 RNAi in nephrocytes entailed defective delivery of slit diaphragm protein to the membrane, whereas RAB11 overexpression revealed a partial phenotypic overlap to Tbc1d8b loss of function.ConclusionsNovel mutations in TBC1D8B are monogenic causes of SRNS. This gene inhibits RAB11. Our findings suggest that RAB11-dependent vesicular nephrin trafficking plays a role in the pathogenesis of nephrotic syndrome.

scholarly journals Advanced Oxidation Protein Products Contribute to Renal Tubulopathy via Perturbation of Renal Fatty Acids

Kidney360 ◽  
2020 ◽  
Vol 1 (8) ◽  
pp. 781-796
Author(s):  
Tadashi Imafuku ◽  
Hiroshi Watanabe ◽  
Takao Satoh ◽  
Takashi Matsuzaka ◽  
Tomoaki Inazumi ◽  
...  
Keyword(s):  
Fatty Acids ◽  
Er Stress ◽  
Advanced Oxidation ◽  
Advanced Oxidation Protein Products ◽  
Fa Composition ◽  
Renal Tubulopathy ◽  
Proximal Tubular ◽  
Proximal Tubulopathy ◽  
Tubular Toxicity

BackgroundRenal proximal tubulopathy plays a crucial role in kidney disease, but its molecular mechanism is incompletely understood. Because proximal tubular cells consume a lot of energy during reabsorption, the relationship between fatty acids (FAs) and proximal tubulopathy has been attracting attention. The purpose of this study is to investigate the association between change in renal FA composition and tubulopathy.MethodsMice with cisplatin-induced nephrotoxicity were used as a model of AKI and 5/6-nephrectomized mice were used as a model of CKD. Renal FA composition in mice was measured by GC-MS. Human tubular epithelial cells (HK-2 cells) were used for in vitro studies.ResultsIn kidneys of AKI mice, increased stearic acid (C18:0) and decreased palmitic acid (C16:0) were observed, accompanied by increased expression of the long-chain FA elongase Elovl6. Similar results were also obtained in CKD mice. We show that C18:0 has higher tubular toxicity than C16:0 via induction of ER stress. Using adenovirus-expressing Elovl6 or siRNA for Elovl6 in HK-2 cells, we demonstrated that increased Elovl6 expression contributes to tubulopathy via increasing C18:0. Elovl6 knockout suppressed the increased serum creatinine levels, renal ER stress, and inflammation that would usually result after 5/6 nephrectomy. Advanced oxidation protein products (AOPPs), specifically an oxidized albumin, was found to induce Elovl6 via the mTORC1/SREBP1 pathway.ConclusionsAOPPs may contribute to renal tubulopathy via perturbation of renal FAs through induction of Elovl6. The perturbation of renal FAs induced by the AOPPs-Elovl6 system could be a potential target for the treatment of tubulopathy.

scholarly journals Contribution of non-coding mutations to RPGRIP1-mediated inherited retinal degeneration

2017 ◽  
Author(s):  
Farzad Jamshidi ◽  
Emily M. Place ◽  
Sudeep Mehrotra ◽  
Daniel Navarro-Gomez ◽  
Mathew Maher ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Clinical Decision Making ◽  
Clinical Decision ◽  
Amplicon Sequencing ◽  
Genetic Diagnostics ◽  
Loss Of Function ◽  
Gene Therapies ◽  
Retinal Degenerations ◽  
Whole Exome

AbstractPurposeWith the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be identified using exon-based sequencing for a significant portion of patients. We hypothesized that non-coding mutations contribute significantly to the genetic causality of IRDs and evaluated patients with single coding mutations in RPGRIP1 to test this hypothesis.MethodsIRD families underwent targeted panel sequencing. Unsolved cases were explored by whole exome and genome sequencing looking for additional mutations. Candidate mutations were then validated by Sanger sequencing, quantitative PCR, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing.ResultsAmong 1722 families, three had biallelic loss of function mutations in RPGRIP1 while seven had a single disruptive coding mutation. Whole exome and genome sequencing revealed potential non-coding mutations in these seven families. In six, the non-coding mutations were shown to lead to loss of function in vitro.ConclusionNon-coding mutations were identified in 6 of 7 families with single coding mutations in RPGRIP1. The results suggest that non-coding mutations contribute significantly to the genetic causality of IRDs and RPGRIP1–mediated IRDs are more common than previously thought.

scholarly journals Early-onset autoimmunity associated with SOCS1 haploinsufficiency

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Jérôme Hadjadj ◽  
Carla Noemi Castro ◽  
Maud Tusseau ◽  
Marie-Claude Stolzenberg ◽  
Fabienne Mazerolles ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Early Onset ◽  
Interferon Γ ◽  
Cytokine Signaling ◽  
Loss Of Function ◽  
Jak2 Inhibitor ◽  
Whole Exome ◽  
Self Tolerance

Abstract Autoimmunity can occur when a checkpoint of self-tolerance fails. The study of familial autoimmune diseases can reveal pathophysiological mechanisms involved in more common autoimmune diseases. Here, by whole-exome/genome sequencing we identify heterozygous, autosomal-dominant, germline loss-of-function mutations in the SOCS1 gene in ten patients from five unrelated families with early onset autoimmune manifestations. The intracellular protein SOCS1 is known to downregulate cytokine signaling by inhibiting the JAK-STAT pathway. Accordingly, patient-derived lymphocytes exhibit increased STAT activation in vitro in response to interferon-γ, IL-2 and IL-4 that is reverted by the JAK1/JAK2 inhibitor ruxolitinib. This effect is associated with a series of in vitro and in vivo immune abnormalities consistent with lymphocyte hyperactivity. Hence, SOCS1 haploinsufficiency causes a dominantly inherited predisposition to early onset autoimmune diseases related to cytokine hypersensitivity of immune cells.

scholarly journals Transient renal Fanconi syndrome in a Chihuahua exposed to Chinese chicken jerky treats

2015 ◽  
Vol 43 (03) ◽  
pp. 188-192 ◽  
Author(s):  
E. Furman ◽  
J. Leidinger ◽  
D. Brandstetter ◽  
C. Hochleithner ◽  
A. C. Sewell ◽  
...  
Keyword(s):  
North America ◽  
Fanconi Syndrome ◽  
Clinical Signs ◽  
Metabolic Abnormalities ◽  
Renal Fanconi Syndrome ◽  
First Report ◽  
History Of ◽  
Renal Tubular

SummaryTransient Fanconi syndrome without azotemia was diagnosed in a dog and was associated with ingestion of Chinese chicken jerky treats. Fanconi syndrome is a proximal renal tubular defect and a diagnosis was made based upon severe glucosuria with normoglycemia, and severe generalized aminoaciduria. The clinical signs of polyuria and polydipsia as well as the massive urinary metabolic abnormalities resolved after jerky treat withdrawal. While frequently seen in North America and Australia, this is the first report of jerky treat induced Fanconi syndrome in continental Europe. Clinicians should be aware of this potential intoxication and be vigilant for a history of jerky treat consumption in a dog with glucosuria.

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