<i>OCRL1</i> Mutations in Dent 2 Patients Suggest a Mechanism for Phenotypic Variability

Abstract

Background/Aims: Dent disease is an X-linked renal proximal tubulopathy associated with mutations in CLCN5 (Dent 1) or OCRL1 (Dent 2). OCRL1 mutations also cause the oculocerebrorenal syndrome of Lowe. Methods: Dent patients with normal sequence for CLCN5 were sequenced for mutations in OCRL1. By analyzing these and all other OCRL1 mutations reported, a model relating OCRL1 mutations to the resulting disease (Dent 2 or Lowe’s) was developed. Results: Six boys with Dent disease had novel OCRL1 mutations: two missense (R301H, G304E) and four mutations predicted to produce premature termination codons (L56DfsX1, S149X, P161PfsX3, and M170IfsX1). These include one of the original patients reported by Dent and Friedman. Slit lamp examinations revealed early cataracts in only one boy with normal vision. None of these Dent 2 patients had metabolic acidosis; 3 had mild mental retardation. Analysis of all known OCRL1 mutations show that Dent 2 mutations fall into two classes that do not overlap with Lowe mutations. Bioinformatics analyses identified expressed OCRL1 splice variants that help explain the variability of those clinical features that distinguish Dent disease from Lowe syndrome. Conclusions:OCRL1 mutations can cause the renal phenotype of Dent disease, without acidosis or the dramatic eye abnormalities typical of Lowe syndrome. We propose a model to explain the phenotypic variability between Dent 2 and Lowe’s based on distinctly different classes of mutations in OCRL1 producing splice variants.

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

“…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).…”

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

“…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.…”

“…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.…”

“…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.…”

“…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. 10 Recently however, two different OCRL mutations each causing both Dent disease 2 and Lowe syndrome even in the same family have been described. 20 In short, Dent's disease seems to be characterized by a genetic and phenotypic heterogeneity.…”