@article {976,
	title = {Beyond the tubule: pathological variants of , encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease.},
	journal = {Am J Physiol Renal Physiol},
	volume = {319},
	year = {2020},
	month = {2020 12 01},
	pages = {F988-F999},
	abstract = {<p>Pathogenic variants in the  gene, encoding the multiligand receptor megalin, cause a rare autosomal recessive syndrome: Donnai-Barrow/Facio-Oculo-Acoustico-Renal (DB/FOAR) syndrome. Because of the rarity of the syndrome, the long-term consequences of the tubulopathy on human renal health have been difficult to ascertain, and the human clinical condition has hitherto been characterized as a benign tubular condition with asymptomatic low-molecular-weight proteinuria. We investigated renal function and morphology in a murine model of DB/FOAR syndrome and in patients with DB/FOAR. We analyzed glomerular filtration rate in mice by FITC-inulin clearance and clinically characterized six families, including nine patients with DB/FOAR and nine family members. Urine samples from patients were analyzed by Western blot analysis and biopsy materials were analyzed by histology. In the mouse model, we used histological methods to assess nephrogenesis and postnatal renal structure and contrast-enhanced magnetic resonance imaging to assess glomerular number. In megalin-deficient mice, we found a lower glomerular filtration rate and an increase in the abundance of injury markers, such as kidney injury molecule-1 and -acetyl-β-d-glucosaminidase. Renal injury was validated in patients, who presented with increased urinary kidney injury molecule-1, classical markers of chronic kidney disease, and glomerular proteinuria early in life. Megalin-deficient mice had normal nephrogenesis, but they had 19\% fewer nephrons in early adulthood and an increased fraction of nephrons with disconnected glomerulotubular junction. In conclusion, megalin dysfunction, as present in DB/FOAR syndrome, confers an increased risk of progression into chronic kidney disease.</p>},
	keywords = {Adolescent, Adult, Animals, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Genetic Variation, Humans, Kidney Glomerulus, Low Density Lipoprotein Receptor-Related Protein-2, Male, Mice, Mice, Knockout, Middle Aged, Renal Insufficiency, Chronic, Young Adult},
	issn = {1522-1466},
	doi = {10.1152/ajprenal.00295.2020},
	author = {Charlton, Jennifer R and Tan, Weizhen and Daouk, Ghaleb and Teot, Lisa and Rosen, Seymour and Bennett, Kevin M and Cwiek, Aleksandra and Nam, Sejin and Emma, Francesco and Jouret, Fran{\c c}ois and Oliveira, Jo{\~a}o Paulo and Tranebj{\ae}rg, Lisbeth and Frykholm, Carina and Mane, Shrikant and Hildebrandt, Friedhelm and Srivastava, Tarak and Storm, Tina and Christensen, Erik Ils{\o} and Nielsen, Rikke}
}
@article {701,
	title = {Mutations in KIRREL1, a slit diaphragm component, cause steroid-resistant nephrotic syndrome.},
	journal = {Kidney Int},
	volume = {96},
	year = {2019},
	month = {2019 Oct},
	pages = {883-889},
	abstract = {<p>Steroid-resistant nephrotic syndrome is a frequent cause of chronic kidney disease almost inevitably progressing to end-stage renal disease. More than 58 monogenic causes of SRNS have been discovered and majority of known steroid-resistant nephrotic syndrome causing genes are predominantly expressed in glomerular podocytes, placing them at the center of disease pathogenesis. Herein, we describe two unrelated families with steroid-resistant nephrotic syndrome with homozygous mutations in the KIRREL1 gene. One mutation showed high frequency in the European population (minor allele frequency 0.0011) and this patient achieved complete remission following treatment, but later progressed to chronic kidney disease. We found that mutant KIRREL1 proteins failed to localize to the podocyte cell membrane, indicating defective trafficking and impaired podocytes function. Thus, the KIRREL1 gene product has an important role in modulating the integrity of the slit diaphragm and maintaining glomerular filtration function.</p>},
	issn = {1523-1755},
	doi = {10.1016/j.kint.2019.06.016},
	author = {Solanki, Ashish K and Widmeier, Eugen and Arif, Ehtesham and Sharma, Shailza and Daga, Ankana and Srivastava, Pankaj and Kwon, Sang-Ho and Hugo, Hannah and Nakayama, Makiko and Mann, Nina and Majmundar, Amar J and Tan, Wei and Gee, Heon Yung and Sadowski, Caroline E and Rinat, Choni and Becker-Cohen, Rachel and Bergmann, Carsten and Rosen, Seymour and Somers, Michael and Shril, Shirlee and Huber, Tobias B and Mane, Shrikant and Hildebrandt, Friedhelm and Nihalani, Deepak}
}
