Novel OCRL1 Mutations in Patients With the Phenotype of Dent Disease

Utsch, Boris; Bökenkamp, Arend; Benz, Marcus R.; Beşbaş, Nesrin; Dötsch, Jörg; Franke, Ingo; Fründ, Stefan; Gök, Faysal; Höppe, Bernd; Karle, Stephanie M.; Kuwertz-Bröking, Eberhard; Laube, Guido F.; Neb, Margarita; Nuutinen, Matti; Özaltın, Fatih; Rascher, Wolfgang; Ring, Troels; Tasic, Velibor; Wijk, J. A. E. van; Ludwig, Michael

doi:10.1053/j.ajkd.2006.08.018

Cited by 76 publications

(80 citation statements)

References 47 publications

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“…This condition, also referred to as "Lowe syndrome," is a severe X-linked disorder characterized by congenital cataracts (12), kidney readsorption defects caused by proximal tubule dysfunction, cognitive impairment, muscle hypotonia, and autism spectrum behavioral disorders (13,14). The other condition is Dent disease, an X-linked disorder involving kidney defects very similar to those associated with Lowe syndrome but, for reasons not yet known, few other dysfunctions (15)(16)(17)(18)(19).OCRL comprises an N-terminal Pleckstrin Homology (PH) domain followed in sequence by a central inositol 5′-phosphatase domain, an ASPM-SPD-2-Hydin (ASH) domain, and a catalytically inactive RhoGAP (GTPase Activating Protein)-like domain (20). OCRL interacts with several endocytic proteins, including clathrin (20-23), the clathrin adaptor AP2 (21, 24), and several endocytic (e. g., Rab5) (25, 26) and nonendocytic Rab GTPases (20, 26, 27).…”

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confidence: 99%

Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1

Swan

Tomasini

Pirruccello

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

117

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Mutations of the inositol 5′ phosphatase oculocerebrorenal syndrome of Lowe (OCRL) give rise to the congenital X-linked disorders oculocerebrorenal syndrome of Lowe and Dent disease, two conditions giving rise to abnormal kidney proximal tubule reabsorption, and additional nervous system and ocular defects in the case of Lowe syndrome. Here, we identify two closely related endocytic proteins, Ses1 and Ses2, which interact with the ASH-RhoGAP-like (ASPM-SPD-2-Hydin homology and Rho-GTPase Activating Domain-like) domain of OCRL. The interaction is mediated by a short amino acid motif similar to that used by the rab-5 effector APPL1 (Adaptor Protein containing pleckstrin homology [PH] domain, PTB domain and Leucine zipper motif 1) APPL1 for OCRL binding. Ses binding is mutually exclusive with APPL1 binding, and is disrupted by the same missense mutations in the ASHRhoGAP-like domain that also disrupt APPL1 binding. Like APPL1, Ses1 and -2 are localized on endosomes but reside on different endosomal subpopulations. These findings define a consensus motif (which we have called a phenylalanine and histidine [F&H] motif) for OCRL binding and are consistent with a scenario in which Lowe syndrome and Dent disease result from perturbations at multiple sites within the endocytic pathway.Dent disease | endocytosis | Lowe syndrome I nositol phospholipids play a critical regulatory function in cell physiology, including membrane traffic. The interconversion of different phosphoinositide species via the action of kinases and phosphatases plays a key role in the maturation and progression of membranes through different stations of the exocytic and endocytic pathways, coordinating these processes with signaling reactions. Thus, the correct spatial and temporal regulation of these enzymes is of central importance (1, 2). As a consequence, not only the lack of these enzymes but also the disruption of their interactions can have profound effects on cell function and result in pathological conditions (2-9).Two human diseases are caused by mutations in an enzyme that selectively dephosphorylates the inositol ring at the 5′ position, using phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ] and phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P 3 ], two phosphoinositides concentrated in the plasma membrane, as its preferred substrates (10). One such disease is oculocerebrorenal syndrome of Lowe (hence the enzyme name "OCRL") (3, 11). This condition, also referred to as "Lowe syndrome," is a severe X-linked disorder characterized by congenital cataracts (12), kidney readsorption defects caused by proximal tubule dysfunction, cognitive impairment, muscle hypotonia, and autism spectrum behavioral disorders (13,14). The other condition is Dent disease, an X-linked disorder involving kidney defects very similar to those associated with Lowe syndrome but, for reasons not yet known, few other dysfunctions (15)(16)(17)(18)(19).OCRL comprises an N-terminal Pleckstrin Homology (PH) domain followed in sequence by a central inositol 5′-phospha...

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mentioning

confidence: 99%

Two closely related endocytic proteins that share a common OCRL-binding motif with APPL1

Swan

Tomasini

Pirruccello

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

117

View full text Add to dashboard Cite

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“…Excepting very few cases, the OCRL mutations associated with Dent disease 2 do not overlap with those causing Lowe syndrome. 10,20,24 Missense mutations occur in the middle region of the gene (exons 9-15), whereas truncating mutations are found exclusively in the first 7 exons; the OCRL mutations associated with Lowe syndrome are located instead in the 3 0 region of the gene (exons [9][10][11][12][13][14][15][16][17][18][19][20][21][22] and involve all three functional OCRL1 domains, whereas frameshift and nonsense mutations cluster in exons [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]. The different distribution of OCRL mutations in Dent disease 2 and Lowe syndrome suggests a genotype-phenotype correlation that has yet to be thoroughly explored.…”

Section: Resultsmentioning

confidence: 99%

“…The OCRL gene located on chromosome Xq26.1, whose mutations cause Lowe syndrome, has recently been found altered in 20% Dent's patients, 9 but about 20% of patients carry neither CLCN5 nor OCRL mutations. [10][11][12][13] Dent's disease tends to become manifest in childhood or early adult life. It is characterized by LMW proteinuria, hypercalciuria, medullary nephrocalcinosis, nephrolithiasis, other tubular dysfunctions, and renal failure in various combinations.…”

Section: Introductionmentioning

confidence: 99%

“…This milder phenotype is not attributable to less severe changes in protein expression or enzyme activity, as both are significantly reduced or absent. [10][11][12][13] The renal symptoms of Lowe syndrome are very similar to those of Dent's disease, though the characteristics of the patients' tubular dysfunction may differ. To date, there are reports of around 45 patients with Dent disease 2; a minority of them have revealed a few mild extrarenal signs, such as mild intellectual impairment, ocular abnormalities, and short stature.…”

Section: Introductionmentioning

confidence: 99%

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An atypical Dent’s disease phenotype caused by co-inheritance of mutations at CLCN5 and OCRL genes

et al. 2012

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Dent's disease is an X-linked renal tubulopathy caused by mutations mainly affecting the CLCN5 gene. Defects in the OCRL gene, which is usually mutated in patients with Lowe syndrome, have been shown to lead to a Dent-like phenotype called Dent disease 2. However, about 20% of patients with Dent's disease carry no CLCN5/OCRL mutations. The disease's genetic heterogeneity is accompanied by interfamilial and intrafamilial phenotypic heterogeneity. We report on a case of Dent's disease with a very unusual phenotype (dysmorphic features, ocular abnormalities, growth delay, rickets, mild mental retardation) in which a digenic inheritance was discovered. Two different, novel disease-causing mutations were detected, both inherited from the patient's healthy mother, that is a truncating mutation in the CLCN5 gene (A249fs*20) and a donor splice-site alteration in the OCRL gene (c.388 þ 3A4G). The mRNA analysis of the patient's leukocytes revealed an aberrantly spliced OCRL mRNA caused by in-frame exon 6 skipping, leading to a shorter protein, but keeping intact the central inositol 5-phosphatase domain and the C-terminal side of the ASH-RhoGAP domain. Only wild-type mRNA was observed in the mother's leukocytes due to a completely skewed X inactivation. Our results are the first to reveal the effect of an epistatic second modifier in Dent's disease too, which can modulate its expressivity. We surmise that the severe Dent disease 2 phenotype of our patient might be due to an addictive interaction of the mutations at two different genes.

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“…10 Dent-2 disease is caused by mutations in OCRL, the gene previously identified as the cause of the oculo-cerebro-renal syndrome (Lowe syndrome, OMIM 309000). 11,12 Patients show a renal phenotype comparable to Dent-1 disease, except for a lower prevalence of nephrocalcinosis. 9 Dent-2 disease may present with additional (mild) extra-renal features of the Lowe syndrome spectrum, for example, peripheral cataracts, mild cognitive and/or mental impairment, stunted growth and elevated serum CK/LDH levels.…”

Section: Diagnostic Settingmentioning

confidence: 99%