A Splicing Variant in OCRL Gene Might Explain the Second Case of Lowe Syndrome in Iran

: Lowe syndrome is a condition that primarily affects eyes, brain, and kidneys. This disorder follows X-linked recessive mode of inheritance and it occurs in males mainly. Mutations in OCRL (located at Xq25) gene can cause accumulation of phosphatidylinositol bisphosphate and disturbed actin cytoskeleton remodeling. There are 268 mutations in OCRL gene causing Lowe syndrome or Dent disease 2 in HGMD database, however 10 - 20% of Lowe syndrome suspects remain undiagnosed at molecular level. Here we present a male case of Lowe syndrome with characteristic features. Comprehensive clinical examination and genetic counseling were performed. Sanger sequencing was employed to investigate the possible OCRL mutations and we identified a donor splice site variant (NM-000276: c.2469 + 1G > A) in hemizygous state. This is a pathogenic variant according to the ACMG standards and guidelines and might explain the clinical features of the patient. This result is in accordance with the clinical diagnosis of Lowe syndrome and it is absent from ExAC, 1000 G, Iranome, GME, gnomAD Genome databases of healthy controls. In-silico analysis of this splicing variant revealed that the position is highly conserved between species. Splicing prediction tools predicted some changes in splicing pattern of the OCRL transcript, elimination of some protein features, and malfunctioning the OCRL protein as a consequence of this variant. Accordingly, we proposed the c.2469 + 1G > A variant might explain the clinical features in studied patient and be employed for prenatal diagnosis of Lowe syndrome in the family.

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Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease

AJP Cell Physiology ◽

10.1152/ajpcell.00277.2011 ◽

2012 ◽

Vol 302 (10) ◽

pp. C1479-C1491 ◽

Cited By ~ 16

Author(s):

Guojin Wu ◽

Wei Zhang ◽

Tao Na ◽

Haiyan Jing ◽

Hongju Wu ◽

...

Keyword(s):

Phosphatase Activity ◽

Transient Receptor Potential ◽

Expression System ◽

Phosphatidyl Inositol ◽

Dent Disease ◽

Lowe Syndrome ◽

Transient Receptor Potential Vanilloid ◽

Xenopus Laevis Oocyte ◽

Phosphatase Domain ◽

Ocrl Gene

Oculocerebrorenal syndrome of Lowe (OCRL) gene product is a phosphatidyl inositol 4,5-bisphosphate [PI( 4 , 5 )P2] 5-phosphatase, and mutations of OCRL cause Lowe syndrome and Dent disease, both of which are frequently associated with hypercalciuria. Transient receptor potential, vanilloid subfamily, subtype 6 (TRPV6) is an intestinal epithelial Ca2+ channel mediating active Ca2+ absorption. Hyperabsorption of Ca2+ was found in patients of Dent disease with increased Ca2+ excretion. In this study, we tested whether TRPV6 is regulated by OCRL and, if so, to what extent it is altered by Dent-causing OCRL mutations using Xenopus laevis oocyte expression system. Exogenous OCRL decreased TRPV6-mediated Ca2+ uptake by regulating the function and trafficking of TRPV6 through different domains of OCRL. The PI( 4 , 5 )P2 5-phosphatase domain suppressed the TRPV6-mediated Ca2+ transport likely through regulating the PI( 4 , 5 )P2 level needed for TRPV6 function without affecting TRPV6 protein abundance of TRPV6 at the cell surface. The forward trafficking of TRPV6 was decreased by OCRL. The Rab binding domain in OCRL was involved in regulating the trafficking of TRPV6. Knocking down endogenous X. laevis OCRL by antisense approach increased TRPV6-mediated Ca2+ transport and TRPV6 forward trafficking. All seven Dent-causing OCRL mutations examined exhibited alleviation of the inhibitory effect on TRPV6-mediated Ca2+ transport together with decreased overall PI( 4 , 5 )P2 5-phosphatase activity. In conclusion, OCRL suppresses TRPV6 via two separate mechanisms. The disruption of PI( 4 , 5 )P2 5-phosphatase activity by Dent-causing mutations of OCRL may lead to increased intestinal Ca2+ absorption and, in turn, hypercalciuria.

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Genotype Phenotype Correlation in Dent Disease 2 and Review of the Literature: OCRL Gene Pleiotropism or Extreme Phenotypic Variability of Lowe Syndrome?

Genes ◽

10.3390/genes12101597 ◽

2021 ◽

Vol 12 (10) ◽

pp. 1597

Author(s):

Lisa Gianesello ◽

Jennifer Arroyo ◽

Dorella Del Prete ◽

Giovanna Priante ◽

Monica Ceol ◽

...

Keyword(s):

Hot Spot ◽

Phenotypic Variability ◽

Dent Disease ◽

Lowe Syndrome ◽

Missense Mutations ◽

Phenotype Correlation ◽

Mutation Site ◽

Phosphatase Domain ◽

Ocrl Gene ◽

Linker Domain

Dent disease is a rare X-linked renal tubulopathy due to CLCN5 and OCRL (DD2) mutations. OCRL mutations also cause Lowe syndrome (LS) involving the eyes, brain and kidney. DD2 is frequently described as a mild form of LS because some patients may present with extra-renal symptoms (ESs). Since DD2 is a rare disease and there are a low number of reported cases, it is still unclear whether it has a clinical picture distinct from LS. We retrospectively analyzed the phenotype and genotype of our cohort of 35 DD2 males and reviewed all published DD2 cases. We analyzed the distribution of mutations along the OCRL gene and evaluated the type and frequency of ES according to the type of mutation and localization in OCRL protein domains. The frequency of patients with at least one ES was 39%. Muscle findings are the most common ES (52%), while ocular findings are less common (11%). Analysis of the distribution of mutations revealed (1) truncating mutations map in the PH and linker domain, while missense mutations map in the 5-phosphatase domain, and only occasionally in the ASH-RhoGAP module; (2) five OCRL mutations cause both DD2 and LS phenotypes; (3) codon 318 is a DD2 mutational hot spot; (4) a correlation was found between the presence of ES and the position of the mutations along OCRL domains. DD2 is distinct from LS. The mutation site and the mutation type largely determine the DD2 phenotype.

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Clinical features and operative technique of transinfundibular craniopharyngioma

Journal of Neurosurgery ◽

10.3171/2019.3.jns181953 ◽

2020 ◽

Vol 133 (1) ◽

pp. 119-128 ◽

Cited By ~ 2

Author(s):

Bin Tang ◽

ShenHao Xie ◽

GuanLin Huang ◽

ZhiGang Wang ◽

Le Yang ◽

...

Keyword(s):

Clinical Features ◽

Operative Technique ◽

Third Ventricle ◽

Radical Resection ◽

The Third ◽

Expanded Endonasal Approach ◽

Sequencing Studies ◽

Characteristic Features ◽

Mri Study ◽

Adamantinomatous Craniopharyngioma

OBJECTIVETransinfundibular craniopharyngioma (TC) is one of the 4 subtypes of suprasellar craniopharyngioma. In this study, the authors analyzed the clinical features of and operative technique for TC.METHODSA total of 95 consecutive cases of suprasellar craniopharyngioma that had been resected via the endoscopic expanded endonasal approach were retrospectively reviewed. Patients were divided into 2 groups: 34 in the TC group and 61 in the nontransinfundibular craniopharyngioma (NC) group. Clinical and radiographic features, intraoperative findings, histopathological and genetic findings, and surgical outcomes were analyzed and compared between groups.RESULTSCompared with NC, TC was mostly seen in adult patients (97.1%); it was rare in children (2.9%). Clinical presentations tended toward headache, hydrocephalus, and diabetes insipidus. The relatively smaller volume, midline location (consistent with the stalk position), unidentifiable stalk, no shift of the third ventricle, and greater likelihood to involve the third ventricle and cause hydrocephalus were the characteristic features of TC in the preoperative MRI study. According to the degree of vertical extension of the tumor, the 34 TCs could be classified into 3 subtypes: type 1, entity was limited to stalk (n = 2, 5.9%); type 2, tumor extended up to the third ventricle (type 2a) or down to the subdiaphragmatic cavity (type 2b) (n = 23, 67.6%); and type 3, tumor extended in both directions (n = 9, 26.5%). For TC resection, the chiasm–pituitary corridor, lamina terminalis corridor, and pituitary corridor could be used separately or jointly. Most of the TCs originated from the infundibulum–tuber cinereum, grew within and along the long axis of the infundibulum, and the pituitary stalk was not usually preserved in TCs (20.6%), whereas the rate of preservation was higher (80.3%) in NCs. Bilateral hypothalamic injury was found in nearly all TCs if radical resection was performed, whereas the relationship between NCs and hypothalamus was either compression (32.8%) or unilateral invasion (67.2%). Meanwhile, the postoperative endocrine and neuropsychological function outcomes in patients with TC were worse than in patients with NC. The genetic analysis with whole-exome sequencing studies showed no differential mutations of CTNNB1 (β-catenin) and BRAF (V600E) between TC and NC subtypes, but there was a difference between adamantinomatous craniopharyngioma and papillary craniopharyngioma.CONCLUSIONSTC is a special subtype of suprasellar craniopharyngioma, which is remarkably different from NC. Identification of this type of tumor preoperatively is essential for the planning of appropriate surgical approach and degree of excision.

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Faculty Opinions recommendation of The phosphoinositide 3-kinase inhibitor alpelisib restores actin organization and improves proximal tubule dysfunction in vitro and in a mouse model of Lowe syndrome and Dent disease.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.738664573.793585211 ◽

2021 ◽

Author(s):

Kenneth Campellone

Keyword(s):

Mouse Model ◽

Proximal Tubule ◽

Kinase Inhibitor ◽

Dent Disease ◽

Lowe Syndrome ◽

Actin Organization ◽

Phosphoinositide 3 Kinase

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A comparison of splicing assays to detect an intronic variant of the OCRL gene in Lowe syndrome

European Journal of Medical Genetics ◽

10.1016/j.ejmg.2017.08.001 ◽

2017 ◽

Vol 60 (12) ◽

pp. 631-634 ◽

Cited By ~ 10

Author(s):

Keita Nakanishi ◽

Kandai Nozu ◽

Ryugo Hiramoto ◽

Shogo Minamikawa ◽

Tomohiko Yamamura ◽

...

Keyword(s):

Lowe Syndrome ◽

Ocrl Gene

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Laurence Moon Bardet Biedle Syndrome

Medicine Today ◽

10.3329/medtoday.v30i1.35566 ◽

2018 ◽

Vol 30 (1) ◽

pp. 41-43

Author(s):

Md Nazrul Islam ◽

Shamima Akhter ◽

SM Kamal ◽

Sabikun Nahar Chowdhury

Keyword(s):

Retinitis Pigmentosa ◽

Clinical Features ◽

Male Patient ◽

Autosomal Recessive ◽

Wide Spectrum ◽

Genetic Disorder ◽

Learning Difficulties ◽

Multiple Systems ◽

Truncal Obesity ◽

Characteristic Features

Laurence Moon Bardet Biedle syndrome is a rare, autosomal recessive genetic disorder involving multiple systems and has wide spectrum of clinical features. Characteristic features of this disorder are retinitis pigmentosa, polydactyly, truncal obesity and learning difficulties. It may also be associated with hypogonadism in male and complex genitourinary abnormalities in female. We present a case of 33 years male patient having obesity, decreased vision, polydactyly, hypogonadism and retinitis pigmentosa. These clinical features are consistent with Laurence Moon Bardet Biedle syndrome.Medicine Today 2018 Vol.30(1): 41-43

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From lowe syndrome to Dent disease: correlations between mutations of the OCRL1 gene and clinical and biochemical phenotypes

Human Mutation ◽

10.1002/humu.21391 ◽

2011 ◽

Vol 32 (4) ◽

pp. 379-388 ◽

Cited By ~ 78

Author(s):

Haifa Hichri ◽

John Rendu ◽

Nicole Monnier ◽

Charles Coutton ◽

Olivier Dorseuil ◽

...

Keyword(s):

Dent Disease ◽

Lowe Syndrome

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Clinical characteristics and outcome of influenza virus infection among adults hospitalized with severe COVID-19: A retrospective cohort study from Wuhan, China

10.21203/rs.3.rs-50577/v1 ◽

2020 ◽

Author(s):

Xunliang Tong ◽

Xiaomao Xu ◽

Guoyue Lv ◽

He Wang ◽

Anqi Cheng ◽

...

Keyword(s):

Influenza Virus ◽

Cohort Study ◽

Clinical Features ◽

Retrospective Cohort Study ◽

Retrospective Cohort ◽

Influenza Virus Infection ◽

Clinical Feature ◽

Risk Of Death ◽

New City ◽

Characteristic Features

Abstract Background Coronavirus disease 2019 (COVID-19) is an emerging infection disease that rapidly spreads worldwide. Co-infection may occur in some cases of COVID-19, like influenza virus and so on. Clinical features and outcomes of severe COVID-19 patients with co-infection of influenza virus need to be noticed.Methods Retrospective cohort study was performed and total of 140 patients with severe COVID-19 was enrolled in designated wards of Sino-French New City Branch of Tongji Hospital between Feb 8th and March 15th in Wuhan, Hubei province, China. The demographic, clinical features, laboratory indices, treatment and outcomes of these patients were collected and analyzed.Results Of 140 severe COVID-19 hospitalized patients, 73 patients were with median age of 66 years old with identification of influenza virus IgM-positive and 67 patients were with median age of 62 years old in influenza virus IgM-negative. Nearly half of severe COVID-19 patients in this research are male. Majority of the severe COVID-19 patients had chronic underlying conditions. Wheeze was the clinical feature of severe COVID-19 patients with influenza IgM-positive (26.4% vs 9.0%, P = 0.008). On contrary, fatigue or myalgia was the feature of the COVID-19 patients without IgM-positive (38.4% vs 58.2%, P = 0.019). Increased levels of ferritin and prolonging APTT were showed in severe COVID-19 patients without influenza IgM-positive compared with patients in other group with significant differences. Death rate in the group of severe COVID-19 patients with influenza IgM-positive is lower than it in other group with significant differences (4.1% vs 14.9%, P = 0.040). In univariate regression analysis, several factors were associated with higher risk of death, which included LDH, troponin, NT-proBNP, D-dimer, PT, APTT, lymphocytes, platelet and eGFR. However, influenza virus IgM positive was associated with lower risk of death.Conclusions Characteristic features of patients with severe COVID-19 with influenza virus IgM-positive were described. Co-infection may occur during the pandemic of COVID-19, and we need to improve our understanding in order to confront this crisis in the future.

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