-
Cell Communication and Signaling : CCS Dec 2023This study aimed to identify an orcl1 mutation in a patient with Dent-2 Disease and investigate the underlying mechanisms.
BACKGROUND
This study aimed to identify an orcl1 mutation in a patient with Dent-2 Disease and investigate the underlying mechanisms.
METHODS
The ocrl1 mutation was identified through exome sequencing. Knockdown of orcl1 and overexpression of the orcl1 mutant were performed in HK-2 and MPC5 cells to study its function, while flow cytometry measured reactive oxygen species (ROS), phosphatidylserine levels, and cell apoptosis. Scanning electron microscopy observed crystal adhesion, while transmission electron microscopy examined kidney tissue pathology. Laser scanning confocal microscopy was used to examine endocytosis, and immunohistochemical and immunofluorescence assays detected protein expression. Additionally, podocyte-specific orcl1 knockout mice were generated to investigate the role of orcl1 in vivo.
RESULTS
We identified a mutation resulting in the replacement of Histidine with Arginine at position 318 (R318H) in ocrl1 in the proband. orcl1 was widely expressed in the kidney. In vitro experiments showed that knockdown of orcl1 and overexpression of ocrl1 mutant increased ROS, phosphatidylserine exocytosis, crystal adhesion, and cell apoptosis in HK-2 cells. Knockdown of orcl1 in podocytes reduced endocytosis and disrupted the cell cycle while increasing cell migration. In vivo studies in mice showed that conditional deletion of orcl1 in podocytes caused glomerular dysfunction, including proteinuria and fibrosis.
CONCLUSION
This study identified an R318H mutation in orcl1 in a patient with Dent-2 Disease. This mutation may contribute to renal injury by promoting ROS production and inducing cell apoptosis in tubular cells, while disrupting endocytosis and the cell cycle, and promoting cell migration of podocytes. Video Abstract.
Topics: Humans; Animals; Mice; Podocytes; Reactive Oxygen Species; Phosphatidylserines; Oculocerebrorenal Syndrome; Endocytosis; Apoptosis; Cell Cycle
PubMed: 38049819
DOI: 10.1186/s12964-023-01272-4 -
Children (Basel, Switzerland) Jul 2023Löwe syndrome (the oculocerebrorenal syndrome of Löwe, OCRL, OMIM #309000, ORPHA: 534) is a very rare multisystem X-linked disorder characterized by ocular, kidney and...
OBJECTIVES
Löwe syndrome (the oculocerebrorenal syndrome of Löwe, OCRL, OMIM #309000, ORPHA: 534) is a very rare multisystem X-linked disorder characterized by ocular, kidney and nervous system anomalies.
CASE PRESENTATION
We present the first Bulgarian genetically confirmed patient with OCRL. The patient had facial dysmorphism, cryptorchidism, congenital cataracts, nystagmus, delayed physical and mental development, and poor nutritional status. He had severe rickets, metabolic acidosis, hypokalaemia, hypophosphataemia, and low IGF-1 levels at the age of three, in addition to his developmental delay. The molecular-genetic analysis reported a pathogenic variant c.1124A>G, p.H375R in the gene. This variant was inherited from the mother, who was a carrier. Following the diagnosis of OCRL, treatment with potassium citrate, phosphate, and calcitriol was initiated, along with an increase in caloric intake. Following general physical and biochemical improvement, therapy with rhGH started 4 years ago, and current results are presented.
CONCLUSIONS
The patient with Löwe syndrome who was presented with a 6-year follow-up demonstrates the complexity of rare disease cases and the value of multidisciplinary care together with growth hormone treatment for better results in these patients.
PubMed: 37508663
DOI: 10.3390/children10071166 -
Annals of Dermatology Nov 2023Lowe syndrome (LS), also known as oculocerebrorenal syndrome, is an X-linked multisystemic disorder caused by mutations in , which encodes a member of the...
Lowe syndrome (LS), also known as oculocerebrorenal syndrome, is an X-linked multisystemic disorder caused by mutations in , which encodes a member of the inositol-5-phosphatase family. As implied by its name, congenital cataracts, defects in the central nervous system, and renal manifestations are the main symptoms. Early hidradenitis suppurativa (HS) occurrence in Dent disease 2 (DD2), which is a mild variant of LS and shares the gene mutation, has been reported, although not in LS patients. Here, we report a case of HS in a 17-year-old boy with genetically confirmed LS, which suggests that defects in the gene may contribute to HS pathogenesis.
PubMed: 38061729
DOI: 10.5021/ad.22.131