Mitochondrial Defects in Lowe's Oculocerebrorenal Syndrome

Gobernado, J. M.; Lousa, M.; Gimeno, A.; Gonsalvez, Mario

doi:10.1001/archneur.1984.04050140106037

Cited by 20 publications

(4 citation statements)

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“…Muscle involvement in Lowe syndrome includes severe hypotonia, present at birth and absence of deep tendon reflexes [3,4]. Muscle biopsy from two Lowe syndrome patients revealed selective type 1 fiber atrophy and additionally mild type 1 fiber predominance [84], a feature also reported by Gobernado et al [85]. It remains to be elucidated, if these findings contribute to the elevation of serum CK, LDH and aspartate aminotransferase despite normal liver function [86].…”

Section: Muscle Hypotoniamentioning

confidence: 58%

Lowe syndrome/Dent-2 disease: A comprehensive review of known and novel aspects

2015

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The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, cognitive and behavioral impairment and a renal proximal tubulopathy in almost all of the patients. Whereas the ocular manifestations and severe hypotonia are present at birth, the renal involvement appears within the first months of life. Patients show progressive growth retardation and may develop a debilitating arthropathy. Treatment is symptomatic and life span rarely exceeds 40 yr. The causative OCRL gene, encodes an inositol polyphosphate 5-phosphatase. OCRL mutations were not only found in classic Lowe syndrome, but also in milder affected patients, classified as having Dent-2 disease. There is a phenotypic continuum within patients with Dent-2 disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for loss of enzyme function. Researchers have conducted a large amount of work to understand the etiology responsible for the disease. However, the mechanisms leading to the clinical manifestations are still poorly understood and we are far from an effective therapy. In this review, we have included well-established findings and the most recent progress in understanding Lowe syndrome and Dent-2 disease.

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Section: Muscle Hypotoniamentioning

confidence: 58%

Lowe syndrome/Dent-2 disease: A comprehensive review of known and novel aspects

2015

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“…The recombinant Lowe's protein has recently been shown to possess 5-phosphatase activity and hydrolyses PtdIns(4,5)P, to PtdIns(4)P, with much greater affinity than the 75-kDa 5-phosphatase (Zhang et al, 1995). It is of particular interest that previous reports implicate mitochondrial defects in the pathogenesis of Lowe's syndrome (Gobernado et al, 1984).…”

Section: Discussionmentioning

confidence: 99%

Tissue Distribution and Intracellular Localisation of the 75‐kDa Inositol Polyphosphate 5‐Phosphatase

Speed

Matzaris

Bird

et al. 1995

European Journal of Biochemistry

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The 75-kDa inositol polyphosphate 5-phosphatase (75-kDa 5-phosphatase) hydrolyses several important mediators of intracellular calcium homeostasis, including inositol 1,4,5-trisphosphate [Ins(l,4,5) Northern analysis of various human tissues revealed the 75-kDa 5-phosphatase has a ubiquitous expression, where differential splicing may occur in specific tissues. Prominent expression of a 4.4-kb transcript was noted in human lung, thymus, testes and placenta, and a 4.6-kb transcript was observed in heart, brain, kidney, ovary and colon. Determination of the intracellular location of the enzyme by indirect immunofluorescence, demonstrated that the 75-kDa 5-phosphatase was associated with mitochondrial and cytosolic cellular compartments. Immunoprecipitation of the total cell homogenate of human lung carcinoma cells (A549) with anti-(recombinant 75-kDa 5-phosphatase) antibodies revealed that the 75-kDa 5-phosphatase is the major PtdIns(4,5)P2 5-phosphatase in this cell line. Analysis of PtdIns(4,5)P2 5-phosphatase activity in subcellular fractions of A549 cells revealed peak 75-kDa 5-phosphatase enzyme activity in the cytosolic and mitochondrial enriched fractions. Immunoblot analysis further confirmed the mitochondrial location of the enzyme.This study demonstrates the tissue distribution and intracellular location of the 75-kDa 5-phosphatase and reveals a novel location for an enzyme involved in phosphatidylinositol turnover.Keywords: inositol polyphosphate 5-phosphatase; inositol 1,4,5-trisphosphate.Sequential phosphorylation of the ubiquitous membrane phospholipid, phosphatidylinositol (PtdIns) by a phosphatidylinositol-4-kinase and a phosphatidylinositol 4-phosphate 5-kinase results in the production of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P21, which serves as a precursor for a number of second messenger molecules (Brockerhoff and Ballou, 1962). Upon receptor activation, PtdIns(4,5)P2 is hydrolysed by phospholipase C yielding inositol 1,4,5-trisphosphate [Ins(1,4,5)P,] and diacylglycerol which serve to mobilise intracellular calcium and activate protein kinase C, respectively (Berridge, 1983;Berridge and Irvine, 1984, 1989;Nishizuka, 1988). In addition, Ins( 1,4,5)P, can be phosphorylated by an Ins( 1,4,5)P, 3-kinase to form inositol 1,3,4,5-tetrakisphosphate [Ins(l,3,4,5)P41, which is implicated in gating calcium at the plasma membrane (Batty Correspondence to

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“…Additionally, increased serum AST and LDH concentrations were noted, while liver function remained within normal ranges [28] . A biochemical study revealed mitochondrial dysfunction is one of the causes through muscle biopsy sample examinations [29] . Eujin Park et al…”

Section: Clinical Ndingsmentioning

confidence: 99%

Atypical phenotypes and novel OCRL variations in southern Chinese patients with Lowe syndrome

Du,

Zhou,

Chen

et al. 2024

Pediatr Nephrol

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Background: Lowe syndrome is an uncommon genetic disorder that follows an X-linked recessive inheritance pattern. It is de ned by the occurrence of congenital cataracts, psychomotor retardation, and dysfunctional proximal renal tubules. This study examined the clinical and genetic features of eight children diagnosed with Lowe syndrome in Southern China.Methods: Whole-exome sequencing was performed on eight Lowe syndrome patients from three medical institutes in Southern China, and clinical and genetic data were collected and analyzed retrospectively.Results: In our cohort, the clinical symptoms of the eight Lowe syndrome individuals varied. One patient was diagnosed with Lowe syndrome but did not have congenital cataracts. All patients had psychomotor retardation, short stature, low molecular weight proteinuria, and albuminuria. The clinical characteristics also included elevated creatine kinase (CK)/ aspartate aminotransferase (AST)/ lactate dehydrogenase (LDH) (87.5%), cryptorchidism (66.7%), renal rickets (37.5%), renal tubular acidosis (37.5%), phosphaturia (37.5%), hypercalciuria (37.5%), nephrocalcinosis (25%) and glycosuria (25%). Eight variations in OCRLwere identi ed in all eight patients with Lowe syndrome, involving three known and ve novel variations. All variations are located in exons 8-23 and occur in functional domains. Three novel nonsense variations were classi ed as pathogenic. Two patients with novel missense variations classi ed as uncertain signi cance showed typical severe phenotypes.Conclusion: This study describes the rst case of an atypical Lowe syndrome patient without congenital cataracts in China and identi es novel OCRL gene variants, which broadens the genetic and symptomatic range for Lowe syndrome.have nonsense, frameshift, or splicing variations, the expression of the OCRL transcript or protein is drastically reduced [14] . These results imply that decreased OCRL expression may contribute to the development of Lowe syndrome.Variations in OCRL are also reported in milder affected patients with Dent-2 disease (OMIM #300555), which typically lacks extrarenal manifestations like cataracts or psychomotor retardation [14,[17][18][19][20] . The observed clinical spectrum among patients with Dent-2 disease and Lowe syndrome indicates individual variation in enzyme function loss compensation [20] . However, the explanations for some OCRL variants manifesting with the respective phenotypic range remain unknown.This study provides a detailed description of the clinical symptoms and genetic characteristics observed in eight Chinese children diagnosed with Lowe syndrome. One of the Lowe syndrome patients with the atypical phenotype had moderate mental retardation and proximal renal tubular dysfunction but no cataracts. We identi ed ve novel variations of the OCRL gene that have not been reported. Two novel missense variations classi ed as uncertain signi cance exhibited typical severe phenotypes. Therefore, we intend to raise clinical pediatricians' awareness and attention to this disease, i...

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Mitochondrial Defects in Lowe's Oculocerebrorenal Syndrome

Cited by 20 publications

References 18 publications

Lowe syndrome/Dent-2 disease: A comprehensive review of known and novel aspects

Lowe syndrome/Dent-2 disease: A comprehensive review of known and novel aspects

Tissue Distribution and Intracellular Localisation of the 75‐kDa Inositol Polyphosphate 5‐Phosphatase

Atypical phenotypes and novel OCRL variations in southern Chinese patients with Lowe syndrome

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