Muscle involvement in Dent disease 2

Park, Eujin; Choi, Hyun Jin; Lee, Jiwon M.; Ahn, Yo Han; Kang, Hee Gyung; Choi, Yoo Mee; Park, Se Jin; Cho, Hee Yeon; Park, Yong Hoon; Lee, Seung Joo; Ha, Il Soo; Cheong, Hae Il

doi:10.1007/s00467-014-2841-4

Cited by 13 publications

(8 citation statements)

References 23 publications

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“…Deep phenotyping analyses unveiled a defective locomotricity in Ocrl Y/− mice, which reflects a global impairment of the muscular apparatus, as indicated by the increased plasma activity of protein CK and atrophy of several hind limb muscles. This phenotype was reminiscent of the muscle hypotonia associated with Lowe syndrome and therefore highly relevant (45). Whether this defective muscular/motor pattern originates from a primary myopathy or is rather a consequence of neurological alterations and how OCRL contributes in maintaining muscular tone remains to be further investigated.…”

Section: Discussionmentioning

confidence: 99%

OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease

Festa

Berquez

Gassama

et al. 2018

Human Molecular Genetics

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Mutations in OCRL encoding the inositol polyphosphate 5-phosphatase OCRL (Lowe oculocerebrorenal syndrome protein) disrupt phosphoinositide homeostasis along the endolysosomal pathway causing dysfunction of the cells lining the kidney proximal tubule (PT). The dysfunction can be isolated (Dent disease 2) or associated with congenital cataracts, central hypotonia and intellectual disability (Lowe syndrome). The mechanistic understanding of Dent disease 2/Lowe syndrome remains scarce due to limitations of animal models of OCRL deficiency. Here, we investigate the role of OCRL in Dent disease 2/Lowe syndrome by using Ocrl Y/− mice, where the lethal deletion of the paralogue Inpp5b was rescued by human INPP5B insertion, and primary culture of proximal tubule cells (mPTCs) derived from Ocrl Y/− kidneys. The Ocrl Y/− mice show muscular defects with dysfunctional locomotricity and present massive urinary losses of low-molecular-weight proteins and albumin, caused by selective impairment of receptor-mediated endocytosis in PT cells. The latter was due to accumulation of phosphatidylinositol 4,5–bisphosphate PI(4,5)P 2 in endolysosomes, driving local hyper-polymerization of F-actin and impairing trafficking of the endocytic LRP2 receptor, as evidenced in Ocrl Y/− mPTCs. The OCRL deficiency was also associated with a disruption of the lysosomal dynamic and proteolytic activity. Partial convergence of disease-pathways and renal phenotypes observed in Ocrl Y/− and Clcn5 Y/− mice suggest shared mechanisms in Dent diseases 1 and 2. These studies substantiate the first mouse model of Lowe syndrome and give insights into the role of OCRL in cellular trafficking of multiligand receptors. These insights open new avenues for therapeutic interventions in Lowe syndrome and Dent disease.

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Section: Discussionmentioning

confidence: 99%

OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease

Festa

Berquez

Gassama

et al. 2018

Human Molecular Genetics

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“…Park et al suggested measuring creatine phosphokinase (CPK) and lactic dehydrogenase (LDH) to discriminate between DD1 and DD2 (Park et al 2014 ). This is because children with DD2 often reportedly had high serum levels of these two muscle enzymes, while this was true of only a few children with DD1 (Utsch et al 2006 ).…”

Section: Phenotypic Heterogeneity Of Dent Diseasementioning

confidence: 99%

Genetics and phenotypic heterogeneity of Dent disease: the dark side of the moon

et al. 2020

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Dent disease is a rare genetic proximal tubulopathy which is under-recognized. Its phenotypic heterogeneity has led to several different classifications of the same disorder, but it is now widely accepted that the triad of symptoms low-molecular-weight proteinuria, hypercalciuria and nephrocalcinosis/nephrolithiasis are pathognomonic of Dent disease. Although mutations on the CLCN5 and OCRL genes are known to cause Dent disease, no such mutations are found in about 25-35% of cases, making diagnosis more challenging. This review outlines current knowledge regarding Dent disease from another perspective. Starting from the history of Dent disease, and reviewing the clinical details of patients with and without a genetic characterization, we discuss the phenotypic and genetic heterogeneity that typifies this disease. We focus particularly on all those confounding clinical signs and symptoms that can lead to a misdiagnosis. We also try to shed light on a concealed aspect of Dent disease. Although it is a proximal tubulopathy, its misdiagnosis may lead to patients undergoing kidney biopsy. In fact, some individuals with Dent disease have high-grade proteinuria, with or without hematuria, as in the clinical setting of glomerulopathy, or chronic kidney disease of uncertain origin. Although glomerular damage is frequently documented in Dent disease patients' biopsies, there is currently no reliable evidence of renal biopsy being of either diagnostic or prognostic value. We review published histopathology reports of tubular and glomerular damage in these patients, and discuss current knowledge regarding the role of CLCN5 and OCRL genes in glomerular function.

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“…The hypotonia is of central origin, although muscle biopsy in two brothers demonstrated selective type-1 fiber atrophy resembling congenital fiber type disproportion myopathy [22], and creatine kinase and/or lactate dehydrogenase levels are typically elevated in Lowe syndrome and to a lesser extent in Dent-2 disease [7, 23, 24]. Decreased motor tone results in delayed motor milestones (75 % of patients achieve independent ambulation by the age of 6–13 years) [15].…”

Section: Clinical Manifestations and Managementmentioning

confidence: 99%

The oculocerebrorenal syndrome of Lowe: an update

2016

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The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, intellectual disability, and proximal renal tubular dysfunction. Whereas the ocular manifestations and severe muscular hypotonia are the typical first diagnostic clues apparent at birth, the manifestations of incomplete renal Fanconi syndrome are often recognized only later in life. Other characteristic features are progressive severe growth retardation and behavioral problems, with tantrums. Many patients develop a debilitating arthropathy. Treatment is symptomatic, and the life span rarely exceeds 40 years. The causative oculocerebrorenal syndrome of Lowe gene (OCRL) encodes the inositol polyphosphate 5-phosphatase OCRL-1. OCRL variants have not only been found in classic Lowe syndrome, but also in patients with a predominantly renal phenotype classified as Dent disease type 2 (Dent-2). Recent data indicate that there is a phenotypic continuum between Dent-2 disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for the loss of enzyme function. Extensive research has demonstrated that OCRL-1 is involved in multiple intracellular processes involving endocytic trafficking and actin skeleton dynamics. This explains the multi-organ manifestations of the disease. Still, the mechanisms underlying the wide phenotypic spectrum are poorly understood, and we are far from a causative therapy. In this review, we provide an update on clinical and molecular genetic findings in Lowe syndrome and the cellular and physiological functions of OCRL-1.

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Muscle involvement in Dent disease 2

Abstract: The serum levels of muscle enzymes in patients with Dent disease can be used as a biomarker to predict genotypes, even though the patients do not have clinical symptoms of muscle involvement.

Cited by 13 publications

References 23 publications

OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease

OCRL deficiency impairs endolysosomal function in a humanized mouse model for Lowe syndrome and Dent disease

Genetics and phenotypic heterogeneity of Dent disease: the dark side of the moon

The oculocerebrorenal syndrome of Lowe: an update

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