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

Recker, Florian; Reutter, Heiko; Ludwig, Michael

doi:10.3233/pge-13049

Cited by 24 publications

(27 citation statements)

References 145 publications

(275 reference statements)

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“…Manifestation of a more complete phenotype has been reported in a total of ten cases and has been attributed to either cytogenetic abnormalities (reciprocal translocation involving the X-chromosome), a 45,X karyotype, uniparental disomy, or an extremely skewed X-inactivation [83]. …”

Section: Female Carriersmentioning

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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Section: Female Carriersmentioning

confidence: 99%

The oculocerebrorenal syndrome of Lowe: an update

2016

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“…This lethal X-linked disease was later found to be caused by mutations in the OCRL1 gene 34 and is known to affect approximately 1 in 500,000 births. 67 LS is characterized by mental retardation, congenital bilateral cataracts, and renal dysfunction. 68 Kidney symptoms include LMW proteinuria, renal proximal tubule acidosis, hypercalciuria, and hypokalemia.…”

Section: Lowe Syndrome Versus Dent-2 Diseasementioning

confidence: 99%

Role of Ocrl1 and Inpp5E in primary cilia assembly and maintenance: a phosphatidylinositol phosphatase relay system?

Madhivanan¹,

Ramadesika²,

Aguilar

2016

RRB

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Abstract:The primary cilium (PC) is a plasma membrane-derived structure of great importance for cell and organismal physiology. Indeed, abnormalities in assembly or function of the PC trigger the onset of a group of genetic diseases collectively known as ciliopathies. In recent years, it has become evident that the integrity and function of the PC depends substantially on signaling elements such as phosphoinositides (PI) and their regulators. Because phospholipids such as PI(4,5)P 2 constitute recruitment platforms for cytoskeleton, signaling, and trafficking machinery, control over their levels is critical for PC function. Although information about phosphoinositol phosphate (PIP) kinases in the PC is scarce, a growing body of evidence supports a role for PIP phosphatases in cilia assembly/maintenance. Indeed, deficiencies in two 5′ PIP phosphatases, Inpp5E and Ocrl1, are clearly linked to ciliopathies like Joubert/MORM syndromes, or ciliopathy-associated dise ases like Lowe syndrome. Here, we review the unique roles of these proteins and their specific site of action for ensuring ciliary integrity. Further, we discuss the possibility that a phosphatase relay system able to pass PI control from a preciliary to an intraciliary compartment is in place to ensure PC integrity/function.

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“…It contains 24 exons including exon 18a, which is alternatively spliced and mostly expressed in brain (4,6). Lowe syndrome affects almost exclusively males, although a few female carriers with the clinical symptoms of the disease have been reported (7,8). Interestingly, some mutations of the OCRL gene cause Dent-2 disease (OMIM #300555), which presents a similar proximal tubule dysfunction but only mild or no additional clinical defects (9)(10)(11).…”

Section: Introductionmentioning

confidence: 99%

Two new missense mutations in the protein interaction ASH domain of OCRL1 identified in patients with Lowe syndrome

Perdomo‐Ramirez

Antón‐Gamero

Rizzo³

et al. 2020

IRDR

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The oculocerebrorenal syndrome of Lowe is a rare X-linked disease characterized by congenital cataracts, proximal renal tubulopathy, muscular hypotonia and mental impairment. This disease is caused by mutations in the OCRL gene encoding membrane bound inositol polyphosphate 5-phosphatase OCRL1. Here, we examined the OCRL gene of two Lowe syndrome patients and report two new missense mutations that affect the ASH domain involved in protein-protein interactions. Genomic DNA was extracted from peripheral blood of two non-related patients and their relatives. Exons and flanking intronic regions of OCRL were analyzed by direct sequencing. Several bioinformatics tools were used to assess the pathogenicity of the variants. The threedimensional structure of wild-type and mutant ASH domains was modeled using the online server SWISS-MODEL. Clinical features suggesting the diagnosis of Lowe syndrome were observed in both patients. Genetic analysis revealed two novel missense variants, c.1907T>A (p.V636E) and c.1979A>C (p.H660P) in exon 18 of the OCRL gene confirming the clinical diagnosis in both cases. Variant c.1907T>A (p.V636E) was inherited from the patient's mother, while variant c.1979A>C (p.H660P) seems to have originated de novo. Analysis with bioinformatics tools indicated that both variants are pathogenic. Both amino acid changes affect the structure of the OCRL1 ASH domain. In conclusion, the identification of two novel missense mutations located in the OCRL1 ASH domain may shed more light on the functional importance of this domain. We suggest that p.V636E and p.H660P cause Lowe syndrome by disrupting the interaction of OCRL1 with other proteins or by impairing protein stability.

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

Cited by 24 publications

References 145 publications

The oculocerebrorenal syndrome of Lowe: an update

The oculocerebrorenal syndrome of Lowe: an update

Role of Ocrl1 and Inpp5E in primary cilia assembly and maintenance: a phosphatidylinositol phosphatase relay system?

Two new missense mutations in the protein interaction ASH domain of OCRL1 identified in patients with Lowe syndrome

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