Renal manifestations of Dent disease and Lowe syndrome

Abstract

To date, two responsible genes for the development of Dent disease have been identified: CLCN5 and OCRL1. In this study, genotype-phenotype correlations were studied in patients with Dent disease and those with Lowe syndrome. Among the 12 boys with a phenotype typical of Dent disease, nine had a mutation in CLCN5 (Dent disease 1), two had a mutation in OCRL1 (Dent disease 2), and one had no mutations in either gene. All seven boys with a clinical diagnosis of Lowe syndrome had a mutation in OCRL1. Patients with Lowe syndrome showed more frequent hypophosphatemia/rickets and more prominent tubular proteinuria than patients with Dent disease 1, and patients with Dent disease 2 had higher degree of tubular proteinuria and hypercalciuria than patients with Dent disease 1. Additionally, one patient with Dent disease 2 showed a mild degree of developmental delay, elevated serum muscle enzyme levels, and cryptorchidism. In this study, the genetic heterogeneity in Dent disease and the phenotypic heterogeneity in Lowe syndrome were confirmed. In patients with Dent disease, the presence of the above-mentioned extrarenal manifestations indicates that it is more likely that the patient is affected by Dent disease 2 than by Dent disease 1.

Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets

“…10,11 The second type is X-linked recessive HR (MIM 300554), characterised by proximal renal tubulopathy and Fanconi syndrome caused by a mutation in the gene coding for the chloride channel 5 (CLCN5; MIM 300008). 12,13 Current recommendations on medical treatment of the HR types without hypercalciuria are intermittent oral phosphate supplementation in combination with alfacalcidol, carefully adjusted to avoid the development of secondary hyperparathyroidism or nephrocalcinosis. 14 Medical treatment improves the bowing of extremities and the stunted growth in children, and prevents the recurring dental abscesses and the dentin malformation, but early treatment onset is crucial for obtaining sufficient efficacy.…”

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.…”

“…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.…”

“…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.…”