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Novel OCRL mutations in Chinese children with Lowe syndrome 
Novel OCRL mutations in Chinese children with Lowe syndrome
  Yan-Qin Zhang, Fang Wang, Jie Ding, Hui Yan, Yan-Ling Yang
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Novel OCRL mutations in Chinese children with Lowe syndrome

Yan-Qin Zhang, Fang Wang, Jie Ding, Hui Yan, Yan-Ling Yang

Beijing, China

Author Affiliations: Department of Pediatrics, Peking University First Hospital, Beijing, China (Zhang YQ, Wang F, Ding J, Yan H, Yang YL)

Corresponding Author: Ding J, MD, PhD, Department of Pediatrics, Peking University First Hospital, 100034 Beijing, China (Tel: 86-010 -83572168; Fax: 86-010-66530532; Email: djnc_5855@126.com)

doi: 10.1007/s12519-013-0406-4

Background: Lowe syndrome is a rare X-linked recessive hereditary disease caused by mutations of the OCRL gene, which encodes an inositol polyphosphate-5-phosphatase. The disease is clinically characterized by congenital cataracts, psychomotor retardation, and proximal tubulopathy.

Methods: We retrospectively reviewed three unrelated Chinese patients with Lowe syndrome, clinically diagnosed by the abnormalities of eyes, nervous system, and kidneys. Genetic analysis of the OCRL gene was done for the three patients as well as their family members.

Results: Three OCRL gene mutations were detected in our study. Two of the mutations, g.1897delT in exon 18 (patient 1) and g.1470delG in exon 15 (patient 2), were novel. A missense mutation (p.Y513C) in exon 15, which had been reported previously, was found in patient 3. The mothers of all patients were heterozygous carriers of the respective mutations.

Conclusions: Three Chinese children were diagnosed with Lowe syndrome through clinical and genetic analyses. And two novel mutations in the OCRL gene were identified.

Key words: cataract; Dent disease 2; Lowe syndrome; mutations; OCRL

World J Pediatr 2013;9(1):53-57


Lowe syndrome (oculo-cerebro-renal syndrome) is a rare X-linked genetic disease seen in approximately 1/200 000-1/500 000 births.[1] The clinical characteristics of Lowe syndrome were eye anomalies (congenital cataracts, infantile glaucoma) resulting in impaired vision, neurological deficits (infantile hypotonia with subsequent mental impairment), and renal tubular dysfunction of the Fanconi type.[2] The hallmark of the disease is the presence of prenatally developed cataracts. There are other frequently noted findings in Lowe syndrome, including absent deep tendon reflexes, maladaptive behaviors, hypercalciuria with nephrocalcinosis and nephrolithiasis, pathologic fractures and bone demineralization.[3,4]

The OCRL gene located on chromosome Xq25-q26 was identified responsible for Lowe syndrome, which encodes a phosphatidylinositol 4, 5-bisphosphate-5-phosphatase.[5,6] The protein is deficient in the fibroblasts of patients with Lowe syndrome.[6] Approximately 200 OCRL mutations have been identified so far, and 90% of them are located in 2 hot spots (exons 10-18 and 19-23) in the OCRL gene. However, correlation of the genotype with phenotype of Lowe syndrome has not been established.

We describe here three unrelated Chinese children with Lowe syndrome and report detection of two novel mutations in the OCRL gene.



We retrospectively reviewed three unrelated Chinese patients diagnosed with Lowe syndrome in our hospital in 2011. Lowe syndrome was diagnosed according to clinical manifestations including congenital cataracts, neurological deficits (infantile hypotonia and mental retardation) and kidney anomalies.[2,4,7] The Ethical Committee of Peking University First Hospital approved the project, and informed consents were obtained from the parents.

Mutation analysis

Blood samples were obtained from the three unrelated Chinese patients and their mothers; genomic DNA was isolated using the BloodZol kit (TransGen Biotech, China). The 24 coding exons of OCRL and their flanking intronic sequences were amplified with primers designed using Primer3 (http://frodo.wi.mit.edu/primer3/). The sequence of the primers used for amplification and sequencing of the OCRL exons are shown in Table 1. PCR reactions were performed in a volume of 25 L consisting of 12.5 L 2Taq PCR Master Mix (Tiangen Biotech, China), 1 L 5 mol/L forward primer and reverse primer, respectively, and 1 L 100 ng/L genomic DNA. The amplification of exon 1, 2 was carried out with the condition of 94C for 5 minutes, followed by 38 cycles of 94C for 30 seconds, an annealing step of 65C for 45 seconds, and 72C for 45 seconds, then 72C for 10 minutes. And the other exons were amplified using touchdown PCR under the condition of annealing temperature from 64C to 58C, descending 1C every 2 cycles, annealing at 58C for 26 cycles. Direct sequencing was performed with an ABI 3730XL automatic sequencer using standard methods (SinoGenoMax, China).


Clinical manifestations

All the three patients had bilateral congenital cataracts, and were diagnosed at the age of 9 months (patient 1) and 5 months (patients 2, 3) after birth, respectively. Both patients 2 and 3 had received surgical treatment of cataracts at 5 months of age. Their clinical manifestations are summarized in Table 2. The three patients had hypotonia and severe motor and language development delay. Patient 1 could not hold his head when he was 9 months of age. Patient 2 achieved unsupportive sitting at 1 year of age and independent standing at 2 years of age. Patient 3 could not walk at 4.5 years of age. Patient 1 had feeding difficulties in infancy. All the patients had rickets, and low molecular-weight (LMW) proteinuria was detected in all three patients; patients 2 and 3 had hypercalciuria, and calciuria of patient 1 was not measured. Furthermore, urinary system ultrasonography revealed tiny hyperechogenic foci in the kidneys of the three patients. Elevated lactate dehydrogenase (LDH) was detected in both patients 1 and 3. Elevated creatinine kinase (CK) was detected in patient 1. Besides, all three patients had high aspartate aminotransferase (AST).

Mutation analysis of the OCRL gene

The mutations of the OCRL gene were analyzed in order to confirm the clinical diagnosis of Lowe syndrome. The results of this analysis are summarized in Table 3. Patient 1 had a novel 1-bp deletion mutation (g.1897delT) in exon 18 of the OCRL gene (Fig). Patient 2 had a novel 1-bp deletion mutation (g.1470delG) in exon 15 of the OCRL gene (Fig). Both of the two mutations were novel, and were predicted to result in premature terminations. Patient 3 had a missense mutation (p.Y513C) (Fig), which had been reported previously.[8] The mothers of the three patients were all heterozyous carriers of the respective mutations.


Lowe syndrome is an X-linked multisystemic disease characterized by severe phenotype including bilateral congenital cataract, mental retardation, and proximal tubulopathy. Anomalies of eyes are the hallmark of Lowe syndrome, since dense congenital cataracts could be found in all affected boys and infantile glaucoma in approximately 50%.[4] In this study, the age at diagnosis of three patients was nine months, 2.2 and 4.5 years, respectively. The three patients had congenital cataracts resulting in impaired vision, and infantile hypotonia with subsequent psychomotor retardation, low molecular-weight proteinuria and nephrocalcinosis. All patients had rickets, and none of them had pathological fractures, which are one of the frequently noted findings of Lowe syndrome. Maia and colleagues[9] reported five patients with Lowe syndrome, and their mean age at first consultation was 76.5 months, about 6.4 years. And two of the five patients had a history of pathological fractures. Ke et al[10] reported three patients from two Chinese families with Lowe syndrome, and the diagnostic age was 9, 26 and 32 years, respectively; all the patients had multiple fractures. Thus, pathological fractures should be considered during the follow-up of patients with Lowe syndrome.

Lowe syndrome is caused by mutations in the OCRL gene, which locates on chromosome Xq25-q26 and encodes a phosphatidylinositol 4, 5-bisphosphate-5-phosphatase. The protein is localized predominantly to the Golgi complex. It is hypothesized that deficiency of this enzyme results in dysregulation of Golgi vesicular transport, causing cataracts and abnormal neurological and renal function.[6] There are two major conserved domains in the OCRL protein: a phosphoinositide 5-phosphatase domain and a C-terminal RhoGAP domain.[11] Faucherre and colleagues[12] investigated the RhoGAP domain of OCRL, and found that loss of OCRL may contribute to mental retardation in patients with Lowe syndrome. Besides its PIP2 5-phosphatase activity, OCRL possesses the ability to bind to Rac GTPase, which is involved in neuronal morphogenesis and development of the central nervous system.[13,14] Coon et al[15] found that the cells of patients with Lowe syndrome have defects in the assembly of primary cilia, and this phenotype was reproduced in the cell lines by knock-down of the OCRL gene. The above results showed that there may be a potential mechanism for phenotypic characteristics of Lowe syndrome. Patients with Lowe syndrome have renal tubulopathy as seen in several ciliopathies, but do not develop renal cysts, which remains to be explained. This study provided new avenues for further investigation of pathomechanisms and therapeutic strategies in patients with Lowe syndrome.

Approximately 200 OCRL mutations have been identified so far. In the present study, we identified two novel mutations in the OCRL gene (g.1897delT in exon 18 and g.1470delG in exon 15), which were predicted to truncate the OCRL protein prematurely during translation, and a missense mutation (p.Y513C) in exon 15 reported previously. There were no special clinical characteristics of the two patients with novel mutations, and there was no apparent phenotypic difference between the patients with truncating mutation and missense mutation in our study.

Hoopes and colleagues[16] detected OCRL gene mutations in 13 male patients, who met strict criteria for Dent disease but lacked mutations in CLCN5. They found OCRL mutations in 5 patients, and none of the five patients had eye anomalies, which exist in typical Lowe syndrome. In addition, three of the five patients had mild mental retardation. Dent-2 disease was first reported by Bökenkamp et al.[17] They found that patients with Dent-2 disease showed an intermediate phenotype, including mild peripheral cataract and some degree of mental retardation. Why mutations of the OCRL gene are associated with both Lowe syndrome and Dent-2 disease? Hichri et al[18] reported that the specific mapping of the frameshift and nonsense mutations in exons 1-7 were identified for Dent disease, while the mutations in exons 8-23 were identified for Lowe syndrome. Therefore, the potential mechanism for different clinical expression is alternative initiation codons in the OCRL gene. Recently, Lozanovski and colleagues[19] reported a boy with Dent disease, with mild mental retardation, but without cataracts, had a 4-base deletion mutation (del259-262 TGTT) in exon 5 of the OCRL gene. In our study, the three patients had typical clinical features of Lowe syndrome and mutations in exon 15 and exon 18.

In conclusion, clinical and genetic analysis is valuable for diagnosis of Lowe syndrome as well as for genetic counseling to avoid reoccurrence within the same family.


We greatly appreciate all patients and their families for participating in this study. We thank Dr. Xiao-Yan Zhang from Peking University First Hospital, Beijing, China, for editing the manuscript.

Funding: This study was supported by grants from National Nature Science Foundation (30801252 and 81070545), Beijing Nature Science Foundation (7102148), National "Eleventh Five-Year" Science and Technology Support Project (2006BAI05A07), and National "Twelfth Five-Year" Science and Technology Support Project (No. 2012BAI03B02).

Ethical approval: None declared.

Competing interest: The Ethical Committee of Peking University First Hospital approved the project, and informed consent was obtained from the patients and their family members.

Contributors: Zhang YQ and Wang F contributed equally to this work. Ding J, Wang F, and Zhang YQ designed the study. All authors collected and analyzed the data, wrote the paper and approved the final version of the paper.


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6       Suchy SF, Olivos-Glander IM, Nussabaum RL. Lowe Syndrome, a deficiency of a phosphatidylinositol 4, 5-bisphosphate 5-phosphatase in the Golgi apparatus. Hum Mol Genet 1995;4:2245-2250.

7       Devuyst O, Thakker RV. Dent's disease. Orphanet J Rare Dis 2010;5:28.

8       Lin T, Orrison BM, Suchy SF, Lewis RA, Nussbaum RL. Mutations are not uniformly distributed throughout the OCRL1 gene in Lowe syndrome patients. Mol Genet Metab 1998;64:58-61.

9       Maia ML, do Val ML, Genzani CP, Fernandes FA, de Andrade MC, Carvalhaes JT. Lowe syndrome: report of five cases. J Bras Nefrol 2010;32:216-222.

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11     McCrea HJ, Paradise S, Tomasini L, Addis M, Melis MA, De Matteis MA, et al. All known patient mutations in the ASH-RhoGAP domains of OCRL affect targeting and APPL1 binding. Biochem Biophys Res Commun 2008;369:493-499.

12     Faucherre A, Desbois P, Satre V, Lunardi J, Dorseuil O, Gacon G. Lowe syndrome protein OCRL1 interacts with Rac GTPase in the trans-Golgi network. Hum Mol Genet 2003;12:2449-2456.

13     Luo L. Rho GTPases in neuronal morphogenesis. Nat Rev Neurosci 2000;1:173-180.

14     Takai Y, Sasaki T, Matozaki T. Small GTP-binding proteins. Physiol Rev 2001;81:153-208.

15     Coon BG, Hernandez V, Madhivanan K, Mukherjee D, Hanna CB, Barinaga-Rementeria Ramirez I, et al. The Lowe syndrome protein OCRL1 is involved in primary cilia assembly. Hum Mol Genet 2012;21:1835-1847.

16     Hoopes RR Jr, Shrimpton AE, Knohl SJ, Hueber P, Hoppe B, Matyus J, et al. Dent Disease with mutations in OCRL1. Am J Hum Genet 2005;76:260-267.

17     Bökenkamp A, Böckenhauer D, Cheong HI, Hoppe B, Tasic V, Unwin R, et al. Dent-2 disease: a mild variant of Lowe syndrome. J Pediatr 2009;155:94-99.

18     Hichri H, Rendu J, Monnier N, Coutton C, Dorseuil O, Poussou RV, et al. From Lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes. Hum Mutat 2011;32:379-388.

19     Lozanovski VJ, Ristoska-Bojkovska N, Korneti P, Gucev Z, Tasic V. OCRL1 mutation in a boy with Dent disease, mild mental retardation, but without cataracts. World J Pediatr 2011;7:280-283.

Received March 7, 2012 Accepted after revision July 4, 2012


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