Endocrine and behavioural features of Lowe syndrome and their potential molecular mechanisms

Sena, Cecilia; Iannello, Grazia; Skowronski, Alicja A.; Dannheim, Katelyn; Cheung, Leonard; Agrawal, Pankaj B.; Hirschhorn, Joel N.; Zeitler, Philip; LeDuc, Charles A.; Stratigopoulos, George; Thaker, Vidhu

doi:10.1136/jmedgenet-2022-108490

Cited by 3 publications

(1 citation statement)

References 41 publications

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“…There is no longer a problem with cryptorchidism, and additional surgery is not anticipated. Thus, it is not surprising that in a recent series of 137 patients, Sena et al showed that 15% of patients were favorably treated with rhGH [16].…”

Section: Discussionmentioning

confidence: 99%

Initial Effect of Recombinant Human Growth Hormone Treatment in a Patient with Löwe Syndrome

et al. 2023

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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 OCRL 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. Conclusion: 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.

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Section: Discussionmentioning

confidence: 99%

Initial Effect of Recombinant Human Growth Hormone Treatment in a Patient with Löwe Syndrome

et al. 2023

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Base editing correction of OCRL in Lowe syndrome: ABE-mediated functional rescue in patient-derived fibroblasts

Chen,

Lo,

Liu

et al. 2024

Human Molecular Genetics

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Lowe syndrome, a rare X-linked multisystem disorder presenting with major abnormalities in the eyes, kidneys, and central nervous system, is caused by mutations in OCRL gene (NG_008638.1). Encoding an inositol polyphosphate 5-phosphatase, OCRL catalyzes the hydrolysis of PI(4,5)P2 into PI4P. There are no effective targeted treatments for Lowe syndrome. Here, we demonstrate a novel gene therapy for Lowe syndrome in patient fibroblasts using an adenine base editor (ABE) that can efficiently correct pathogenic point mutations. We show that ABE8e-NG-based correction of a disease-causing mutation in a Lowe patient-derived fibroblast line containing R844X mutation in OCRL gene, restores OCRL expression at mRNA and protein levels. It also restores cellular abnormalities that are hallmarks of OCRL dysfunction, including defects in ciliogenesis, microtubule anchoring, α-actinin distribution, and F-actin network. The study indicates that ABE-mediated gene therapy is a feasible treatment for Lowe syndrome, laying the foundation for therapeutic application of ABE in the currently incurable disease.

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OCRL1 Deficiency Affects the Intracellular Traffic of ApoER2 and Impairs Reelin-Induced Responses

Fuentealba,

Pizarro,

Marzolo

2024

Biomolecules

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Lowe Syndrome (LS) is a rare X-linked disorder characterized by renal dysfunction, cataracts, and several central nervous system (CNS) anomalies. The mechanisms underlying the neurological dysfunction in LS remain unclear, albeit they share some phenotypic characteristics similar to the deficiency or dysfunction of the Reelin signaling, a relevant pathway with roles in CNS development and neuronal functions. In this study, we investigated the role of OCRL1, an inositol polyphosphate 5-phosphatase encoded by the OCRL gene, mutated in LS, focusing on its impact on endosomal trafficking and receptor recycling in human neuronal cells. Specifically, we tested the effects of OCRL1 deficiency in the trafficking and signaling of ApoER2/LRP8, a receptor for the ligand Reelin. We found that loss of OCRL1 impairs ApoER2 intracellular trafficking, leading to reduced receptor expression and decreased levels at the plasma membrane. Additionally, human neurons deficient in OCRL1 showed impairments in ApoER2/Reelin-induced responses. Our findings highlight the critical role of OCRL1 in regulating ApoER2 endosomal recycling and its impact on the ApoER2/Reelin signaling pathway, providing insights into potential mechanisms underlying the neurological manifestations of LS.

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Endocrine and behavioural features of Lowe syndrome and their potential molecular mechanisms

Cited by 3 publications

References 41 publications

Initial Effect of Recombinant Human Growth Hormone Treatment in a Patient with Löwe Syndrome

Initial Effect of Recombinant Human Growth Hormone Treatment in a Patient with Löwe Syndrome

Base editing correction of OCRL in Lowe syndrome: ABE-mediated functional rescue in patient-derived fibroblasts

OCRL1 Deficiency Affects the Intracellular Traffic of ApoER2 and Impairs Reelin-Induced Responses

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