General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. We propose that the promoter mutation alters tissue-specific chromatin loop formation with consequent organ-specific deficiency of PMM2 leading to the restricted phenotype of HIPKD. Our findings extend the spectrum of genetic 5 causes for both HI and PKD and provide insights into gene regulation and PMM2 pleiotropy.6
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. 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. 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. analysis showed that the particular 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. In this novel genetic disorder, fully penetrant heterozygous missense mutations in 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.
Background/Aims: Mutations in the inwardly-rectifying K+-channel KCNJ10/Kir4.1 cause autosomal recessive EAST syndrome (epilepsy, ataxia, sensorineural deafness and tubulopathy). KCNJ10 is expressed in the distal convoluted tubule of the kidney, stria vascularis of the inner ear and brain glial cells. Patients diagnosed clinically with EAST syndrome were genotyped and mutations in KCNJ10 were studied functionally. Methods: Patient DNA was amplified and sequenced, and new mutations were identified. Mutant and wild-type KCNJ10 constructs were cloned and heterologously expressed in Xenopus oocytes. Whole-cell K+ currents were measured by 2-electrode voltage clamping and channel expression was analysed by Western blotting. Results: We identified 3 homozygous mutations in KCNJ10 (p.F75C, p.A167V and p.V91fs197X), with mutation p.A167V previously reported in a compound heterozygous state. Oocytes expressing wild-type human KCNJ10 showed inwardly rectified currents, which were significantly reduced in all of the mutants (p < 0.001). Specific inhibition of KCNJ10 currents by Ba2+ demonstrated a large residual function in p.A167V only, which was not compatible with causing disease. However, co-expression with KCNJ16 abolished function in these heteromeric channels almost completely. Conclusion: This study provides an explanation for the pathophysiology of the p.A167V KCNJ10 mutation, which had previously not been considered pathogenic on its own. These findings provide evidence for the functional cooperation of KCNJ10 and KCNJ16. Thus, in vitro ascertainment of KCNJ10 function may necessitate co-expression with KCNJ16.
Enamel renal syndrome (ERS) is a rare autosomal recessive disorder that still not fully characterized. Here we investigated ERS characteristics in 11 patients from 5 Brazilian families through clinical examination, imaging, renal ultrasonography, laboratory tests and DNA sequencing. The patients' age ranged from 6 to 25 years old, and the presence of hypoplastic amelogenesis imperfecta, microdontia, intra-pulpal calcification, impacted posterior teeth with hyperplastic pericoronal follicles, gingival fibromatosis, ectopic calcifications on gingival and pericoronal tissues, and nephrocalcinosis were common findings to all patients. Only 4 patients showed abnormal laboratory tests (vitamin D, parathyroid hormone, phosphate, calcium).Intellectual disability and renal cysts were present in 2 patients each. Biallelic loss of function mutations in FAM20A gene, characterized by one base pair deletion in exon 11, resulting in a frameshift replacing a glutamine at codon 483 for a lysine and terminating at position 24 [NG_029809.1: c.1447delG; p.(Glu483Lysfs*24)], were detected in all patients, strongly suggesting a founder effect. Our results reinforce the distinct orofacial features of ERS, which are the clue for kidney examination and genetic testing. Early diagnosis is essential to minimize the deleterious effects related to ERS. Here we report the largest series of patients with ERS in the same population, and describe, for the first time, a founder mutation for FAM20A.
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