Dent disease is an X-linked recessive renal tubular disorder, which is mainly caused by mutations of the CLCN5 gene and OCRL gene. It is characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis or nephrolithiasis, and progressive renal failure. Nephrotic syndrome is a glomerular disorder characterized by massive proteinuria, hypoalbuminemia, edema, and hyperlipidemia. In this study, we report two cases of Dent disease manifesting as nephrotic syndrome. Two patients were initially diagnosed with nephrotic syndrome due to edema, nephrotic range proteinuria, hypoalbuminemia, and hyperlipidemia, and responded to prednisone and tacrolimus therapy. Genetic testing revealed mutations in the OCRL and CLCN5 genes. They were eventually diagnosed with Dent disease. Nephrotic syndrome is a rare and insidious phenotype of Dent disease, and its pathogenesis is not fully understood. Patients with nephrotic syndrome are recommended to routinely undergo urinary protein classification and urinary calcium testing, especially those with frequently recurrent nephrotic syndrome and poor response to steroid and immunosuppressive therapy. To date, there is no effective drug treatment for Dent disease. About 30% to 80% of patients progress to end-stage renal disease at the age of 30-50.

Oculocerebrorenal syndrome of Lowe is a rare X-linked disorder characterized by congenital cataracts, mental retardation, and proximal tubulopathy. This condition is caused by a mutation of OCRL gene (located at chromosome Xq26.1), which encodes an inositol polyphosphate 5-phosphatase.
We identified two novel OCRL mutations in two unrelated Chinese boys, each with a severe phenotype of Lowe syndrome. A novel de novo deletion (hemizygous c.659_662delAGGG, p.E220Vfs*29) was present in patient 1 and a novel splicing mutation (hemizygous c.2257-2A > T) that was maternally inherited was present in patient 2. A renal biopsy in patient 2 indicated mild mesangial proliferative glomerulonephritis, mild focal mononuclear cells infiltration, and interstitial focal fibrosis. Moreover, renal expression of OCRL-1 protein in patient 2 was significantly reduced compared to a control patient with thin basement membrane disease.
This study reports two novel OCRL variants associated with severe ocular and neurologic deficiency, despite only mild renal dysfunction. Based on our two patients and a literature review, the genotype-phenotype correlation of OCRL mutations with this severe phenotype of Lowe syndrome suggest a possible clustering of missense, deletion, and nonsense mutations in the 5-phosphatase domain and Rho-GAP domain in the Chinese population.

BACKGROUND: Lowe syndrome is an X-linked multisystem disorder affecting eyes, nervous system, and kidney. The main causes are mutations in the OCRL gene that encodes a member of the inositol polyphosphate-5-phosphatase protein family. In this study, we aimed to gain new insights into the consequences of a novel OCRL intronic variant on pre-mRNA splicing as a main cause of Lowe syndrome in a boy.
METHODS: After clinical diagnosis of the patient with Lowe syndrome, genetic testing was used to detect the presence of the OCRL variants. In silico analysis, human splicing finder and PyMol were used to predict this variant effect. Then, we analyzed the variant transcript by using a minigene construct in addition to in silico analysis.
RESULTS: A hemizygous novel splicing variant in the intron 10 splice donor site of OCRL (c.939 + 3A > C) was identified in a boy with Lowe syndrome. We detected that the splice junction variant leads to aberrant OCRL mRNA splicing which results in the formation of an alternative transcript in which 29 nucleotides of exon 10 were skipped. The findings obtained from the exon-trapping assay were identical to those of in silico analysis. Hence, the truncated OCRL protein may lacked the last 597 native amino acids.
CONCLUSIONS: The minigene assays detected the same transcript abnormality to in silico assay and were reliable in revealing the pathogenicity of the intronic variant we have used previously. Overall, this study provides new insights about Lowe syndrome and further reveals the molecular pathogenicity mechanism of the intronic variant disease.

BACKGROUND: Lowe syndrome is a rare X-linked disease that is characterized by renal dysfunction, developmental delays, congenital cataracts and glaucoma. Mutations in the oculocerebral renal syndrome of Lowe (OCRL) gene are found in Lowe syndrome patients. Although loss of vision is a major concern for families and physicians who take care of Lowe syndrome children, definitive cause of visual loss is still unclear. Children usually present with bilateral dense cataracts at birth and glaucoma, which occurs in more than half of cases, either concurrently or following cataract surgery.
METHODS: A retrospective review was conducted on the prevalence and characteristics of ocular findings among families of patients with Lowe syndrome with 137 uniquely affected individuals.
RESULTS: Of 137 patients, all had bilateral congenital cataracts. Nystagmus was reported in 69.3% of cases, glaucoma in 54.7%, strabismus in 35.0%, and corneal scar in 18.2% of patients. Glaucoma was reported as the most common cause of blindness (46%) followed by corneal scars (41%). Glaucoma occurred in 54.7% of patients and affected both eyes in the majority of cases. Of these patients, 55% underwent surgery for glaucoma, while the remaining patients used medications to control their eye pressure. Timolol and latanoprost were the most commonly used medications. Although trabeculectomy and goniotomy are commonly used for pressure management, aqueous tube shunts had the best outcomes.
CONCLUSIONS: Ocular manifestations in individuals with Lowe syndrome and carriers with OCRL mutation are reported which may help familiarize clinicians with the ocular manifestations and management of a rare and complex syndrome.

BACKGROUND: Dent disease is a rare tubulopathy characterized by manifestations of proximal tubular dysfunction, which occurs almost exclusively in males. It mainly presents symptoms in early childhood and may progress to end-stage renal failure between the 3rd and 5th decades of human life. According to its various genetic basis and to clinical signs and symptoms, researchers define two forms of Dent disease (Dent diseases 1 and 2) and suggest that these forms are produced by mutations in the CLCN5 and OCRL genes, respectively. Dent diseases 1 and 2 account for 60% and 15% of all Dent disease cases, and their genetic cause is generally understood. However, the genetic cause of the remaining 25% of Dent disease cases remains unidentified.
METHODS: All relevant peer-reviewed original articles published thus far have been screened out from PubMed and have been referenced.
RESULTS: Genetic testing has been used greatly to identify mutation types of CLCN5 and OCRL gene, and next-generation sequencing also has been used to identify an increasing number of unknown genotypes. Gene therapy may bring new hope to the treatment of Dent disease. The abuse of hormones and immunosuppressive agents for the treatment of Dent disease should be avoided to prevent unnecessary harm to children.
CONCLUSIONS: The current research progress in classification, genetic heterogeneity, diagnosis, and treatment of Dent disease reviewed in this paper enables doctors and researchers to better understand Dent disease and provides a basis for improved prevention and treatment.

Lowe syndrome is an x-linked disorder characterized by congenital cataracts, nervous system abnormalities and renal tubular dysfunction. With the rising number of reported cases, more patients are found to suffer from endocrine abnormalities. Hereby, three Chinese patients with typical symptoms and extremely short stature were described. The OCRL gene was analyzed. A combination of blood biochemistry and radiological examinations were performed. Growth hormone provocation test was taken in one patient. Nucleotide sequence analysis revealed a de novo novel hemizygous mutation (c.2290_2291delinsCT) in exon 21 in an adolescent boy. As indicated by the growth hormone provocation test, the boy had growth hormone deficiency. The other two patients were brothers with extremely short stature, and manifested the same hemizygous mutation (c.2581G > A) in exon 23. It was speculated that the mutation of OCRL gene could lead to deficiency of growth hormone, for which an early growth hormone intervention may be beneficial.

Lowe syndrome is a rare X-linked syndrome that is characterized by involvement of the eyes, central nervous system, and kidneys. The aim of the present study was to determine the molecular basis of four patients with congenital cataract, infantile congenital hypotonia, and proximal renal tubular defect.
Four children who met the clinical manifestations of Lowe syndrome were enrolled in this study. Patients\' clinical information on eyes, central nervous system, kidneys, and family histories, etc., were reviewed and analyzed. After obtaining informed consent, we performed a mutation analysis of OCRL gene using direct sequencing. Because of failure of PCR amplification, low coverage shortread whole genome sequencing (CNVseq) analysis was performed on one proband. Real-time PCR was subsequently performed to confirm the CNV that was detected from the CNVseq results.
We identified three OCRL allelic variants, including two novel missense mutations (c.1423C>T/p.Pro475Ser, c.1502T>G/p.Ile501Ser) and one recurrent nonsense mutation (c.2464C>T/p.Arg822Ter). Various bioinformatic tools revealed scores associated with potential pathogenic effects for the two missense variants, and protein alignments revealed that both variants affected an amino acid highly conserved among species. Since deletion of the entire gene was suspected in a patient, CNVseq was used, identifying an interstitial deletion to approximately 190 kb, encompassing OCRL, and SMARCA1 gene. Moreover, the hemizygous CNV was confirmed by qPCR. Reviewing another case reported in the literature, we found that the deletion of OCRL and nearby genes may contribute to a more severe phenotype and premature death.
This is the first report of an interstitial deletion encompassing OCRL and SMARCA1 gene in Lowe syndrome. Our results expand the spectrum of mutations of the OCRL gene in Chinese population. Moreover, whole-genome sequencing presents a comprehensive and reliable approach for detecting genomic copy number variation in patients or carriers in the family with rare inherited disorders.

Dent\'s disease is an X-linked recessive proximal tubular disorder that mostly affects male patients in childhood or early adult life. The condition is caused by mutations in the CLCN5 (Dent disease 1) or OCRL (Dent disease 2) genes located on chromosome Xp11.22 and Xq25, respectively. In most male patients, proteinuria is subnephrotic but may reach nephrotic levels. Here, we report the first case of Dent\'s disease complicated by nephrotic syndrome. Dent\'s disease should be considered in the differential diagnosis of nephrotic syndrome, and especially in male patients with early onset of nephrotic syndrome. A urinary α1-microglobulin/albumin ratio > 1 may provide the first clue to a tubulopathy.

BACKGROUND: Lowe syndrome, an X-linked, inheritable disease with clinical symptoms of congenital cataracts, incomplete Fanconi syndrome, and mental retardation, has an approximate incidence of 1 in 500 000. Nearly 200 OCRL mutations related to Lowe syndrome have been found worldwide, with only ten mutations among the Chinese population. Since more mutations may exist in Chinese patients, we sequenced and analyzed the OCRL genes of six children with Lowe syndrome in a medical center in China.
METHODS: Peripheral blood was collected from six children with Lowe syndrome and their relatives, and ten healthy adults. Genomic DNA was extracted from the blood and applied to amplify the twenty-four exons and flanking introns of the OCRL gene. The mutations were identified by sequencing.
RESULTS: Five mutations (c.1528C>T, c.2187insG, c.1366C>T, c.1499G>A, and c.2581G>A) of the OCRL gene were found in five families; c.2187insG and c.1366C>T were novel mutations. None of the five mutations were detected in 20 normal chromosomes. No mutation was found in the sixth family.
CONCLUSIONS: Two novel mutations of the OCRL gene, c.2187insG and c.1366C>T, were found in Chinese patients with Lowe syndrome, which will provide new clues for the etiology of Lowe syndrome and could be beneficial to genetic diagnosis of the condition.