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

Genes ◽  
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.

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

2012 ◽  
Vol 302 (10) ◽  
pp. C1479-C1491 ◽  
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.

scholarly journals A Novel Missense Variant of HOXD13 Caused Atypical Synpolydactyly by Impairing the Downstream Gene Expression and Literature Review for Genotype–Phenotype Correlations

2021 ◽  
Vol 12 ◽  
Author(s):  
Ruiji Guo ◽  
Xia Fang ◽  
Hailei Mao ◽  
Bin Sun ◽  
Jiateng Zhou ◽  
...  
Keyword(s):  
Limb Development ◽  
Missense Variant ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Phenotype Correlation ◽  
Mutation Site ◽  
Genotype Phenotype Correlation ◽  
Α Helix ◽  
Severe Degree ◽  
Hands And Feet

Synpolydactyly (SPD) is a hereditary congenital limb malformation with distinct syndactyly designated as SPD1, SPD2, and SPD3. SPD1 is caused by mutations of HOXD13, which is a homeobox transcription factor crucial for limb development. More than 143 SPD patients have been reported to carry HOXD13 mutations, but there is a lack of genotype–phenotype correlation. We report a novel missense mutation of c. 925A > T (p.I309F) in an individual with atypical synpolydactyly inherited from her father with mild clinodactyly and three other different alanine insertion mutations in HOXD13 identified by whole exome sequencing (WES) in 12 Chinese SPD families. Unlike polyalanine extension, which tends to form α-helix and causes protein aggregation in the cytoplasm as shown by molecular simulation and immunofluorescence, the c. 925A > T mutation impairs downstream transcription of EPHA7. We compiled literature findings and analyzed genotype–phenotype features in 173 SPD individuals of 53 families, including 12 newly identified families. Among the HOXD13-related individuals, mutations were distributed in three regions: polyalanine, homeobox, and non-homeobox. Polyalanine extension was the most common variant (45%), followed by missense mutations (32%) mostly in the homeobox compared with the loss-of-function (LOF) variants more likely in non-homeobox. Furthermore, a more severe degree and classic SPD were associated with polyalanine mutations although missense variants were associated with brachydactyly and syndactyly in hands and feet and LOF variants with clinodactyly in hands. Our study broadens the HOXD13 mutation spectrum and reveals the profile of three different variants and their severity of SPD, the genotype–phenotype correlation related to the HOXD13 mutation site provides clinical insight, including for genetic counseling.

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

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Massoud Houshmand ◽  
Gholamreza Babamohammadi ◽  
Hamidreza Moazzeni ◽  
Ahmad Reza Salehi Chaleshtori ◽  
Mohammad taghi Akbari
Keyword(s):  
Clinical Features ◽  
In Silico Analysis ◽  
Dent Disease ◽  
Lowe Syndrome ◽  
Phosphatidylinositol Bisphosphate ◽  
Splicing Variant ◽  
Ocrl Gene ◽  
Cytoskeleton Remodeling ◽  
Standards And Guidelines ◽  
Characteristic Features

: 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.

scholarly journals Assessment of Sacsin Turnover in Patients With ARSACS: Implications for Molecular Diagnosis and Pathogenesis

Neurology ◽  
2021 ◽  
pp. 10.1212/WNL.0000000000012962
Author(s):  
Fabiana Longo ◽  
Daniele De Ritis ◽  
Annarita Miluzio ◽  
Davide Fraticelli ◽  
Jonathan Baets ◽  
...  
Keyword(s):  
Age Of Onset ◽  
Phenotypic Variability ◽  
Empirical Studies ◽  
Mechanistic Explanation ◽  
Large Set ◽  
Missense Mutations ◽  
Phenotype Correlation ◽  
Gene Encoding ◽  
Genotype Phenotype Correlation ◽  
Protein Reduction

Background and Objectives:Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by mutations in SACS gene encoding sacsin, a huge multimodular protein of unknown function. More than 200 SACS mutations have been described worldwide to date. Since ARSACS presents phenotypic variability, previous empirical studies attempted to correlate the nature and position of SACS mutations with the age of onset or with disease severity, though not considering the effect of the various mutations on protein stability. In this work, we studied genotype-phenotype correlation in ARSACS at a functional level.Methods:We analyzed a large set of skin fibroblasts derived from ARSACS patients, including both new and already published cases, carrying mutations of different type affecting diverse domains of the protein.Results:We found that sacsin is almost absent in ARSACS patients, regardless of the nature of the mutation. As expected, we did not detect sacsin in patients with truncating mutations. Interestingly, we found it strikingly reduced or absent also in compound heterozygotes carrying diverse missense mutations. In this case, we excluded SACS mRNA decay, defective translation or faster post-translational degradation as possible causes of protein reduction. Conversely, our results demonstrate that nascent mutant sacsin protein undergoes cotranslational ubiquitination and degradation.Discussion:Our results provide one mechanistic explanation for the lack of genotype-phenotype correlation in ARSACS. We also propose a new and unambiguous criterion for ARSACS diagnosis, that is based on the evaluation of sacsin level. Finally, we identified preemptive degradation of a mutant protein as a novel cause of a human disease.

Mutation Spectrum in Patients with Wiskott-Aldrich Syndrome and X-linked Thrombocytopenia: Identification of Twelve Different Mutations in the WASP Gene

1996 ◽  
Vol 75 (04) ◽  
pp. 546-550 ◽  
Author(s):  
Marianne Schwartz ◽  
Albert Békássy ◽  
Mikael Donnér ◽  
Thomas Hertel ◽  
Stefan Hreidarson ◽  
...  
Keyword(s):  
Base Pair ◽  
Hot Spot ◽  
Missense Mutations ◽  
Nucleotide Substitutions ◽  
Exon 2 ◽  
Wiskott Aldrich Syndrome ◽  
Base Pair Deletion ◽  
Reliable Diagnosis ◽  
Wasp Gene ◽  
Detection Of Mutations

SummaryTwelve different mutations in the WASP gene were found in twelve unrelated families with Wiskott-Aldrich syndrome (WAS) or X-linked thrombocytopenia (XLT). Four frameshift, one splice, one nonsense mutation, and one 18-base-pair deletion were detected in seven patients with WAS. Only missense mutations were found in five patients diagnosed as having XLT. One of the nucleotide substitutions in exon 2 (codon 86) results in an Arg to Cys replacement. Two other nucleotide substitutions in this codon, R86L and R86H, have been reported previously, both giving rise to typical WAS symptoms, indicating a mutational hot spot in this codon. The finding of mutations in the WASP gene in both WAS and XLT gives further evidence of these syndromes being allelic. The relatively small size of the WASP gene facilitates the detection of mutations and a reliable diagnosis of both carriers and affected fetuses in families with WAS or XLT.

scholarly journals Mutation-specific non-canonical pathway of PTEN as a distinct therapeutic target for glioblastoma

2021 ◽  
Vol 12 (4) ◽  
Author(s):  
Seung Won Choi ◽  
Yeri Lee ◽  
Kayoung Shin ◽  
Harim Koo ◽  
Donggeon Kim ◽  
...  
Keyword(s):  
Functional Properties ◽  
Therapeutic Target ◽  
Medical Center ◽  
Dominant Negative ◽  
The Cancer Genome Atlas ◽  
Dominant Negative Effect ◽  
Cell Periphery ◽  
Missense Mutations ◽  
Phosphatase Domain ◽  
Mutant Proteins

AbstractPTEN is one of the most frequently altered tumor suppressor genes in malignant tumors. The dominant-negative effect of PTEN alteration suggests that the aberrant function of PTEN mutation might be more disastrous than deletion, the most frequent genomic event in glioblastoma (GBM). This study aimed to understand the functional properties of various PTEN missense mutations and to investigate their clinical relevance. The genomic landscape of PTEN alteration was analyzed using the Samsung Medical Center GBM cohort and validated via The Cancer Genome Atlas dataset. Several hotspot mutations were identified, and their subcellular distributions and phenotypes were evaluated. We established a library of cancer cell lines that overexpress these mutant proteins using the U87MG and patient-derived cell models lacking functional PTEN. PTEN mutations were categorized into two major subsets: missense mutations in the phosphatase domain and truncal mutations in the C2 domain. We determined the subcellular compartmentalization of four mutant proteins (H93Y, C124S, R130Q, and R173C) from the former group and found that they had distinct localizations; those associated with invasive phenotypes (‘edge mutations’) localized to the cell periphery, while the R173C mutant localized to the nucleus. Invasive phenotypes derived from edge substitutions were unaffected by an anti-PI3K/Akt agent but were disrupted by microtubule inhibitors. PTEN mutations exhibit distinct functional properties regarding their subcellular localization. Further, some missense mutations (‘edge mutations’) in the phosphatase domain caused enhanced invasiveness associated with dysfunctional cytoskeletal assembly, thus suggesting it to be a potent therapeutic target.

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

2017 ◽  
Vol 60 (12) ◽  
pp. 631-634 ◽  
Author(s):  
Keita Nakanishi ◽  
Kandai Nozu ◽  
Ryugo Hiramoto ◽  
Shogo Minamikawa ◽  
Tomohiko Yamamura ◽  
...  
Keyword(s):  
Lowe Syndrome ◽  
Ocrl Gene

scholarly journals Tumour risks and genotype–phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD

2018 ◽  
Vol 55 (6) ◽  
pp. 384-394 ◽  
Author(s):  
Katrina A Andrews ◽  
David B Ascher ◽  
Douglas Eduardo Valente Pires ◽  
Daniel R Barnes ◽  
Lindsey Vialard ◽  
...  
Keyword(s):  
Succinate Dehydrogenase ◽  
Phenotypic Variability ◽  
Cohort Analysis ◽  
Cumulative Risk ◽  
Clinical Information ◽  
Missense Mutations ◽  
Pathogenic Variants ◽  
Mutation Carriers ◽  
Kaplan Meier ◽  
Age Related

BackgroundGermline pathogenic variants in SDHB/SDHC/SDHD are the most frequent causes of inherited phaeochromocytomas/paragangliomas. Insufficient information regarding penetrance and phenotypic variability hinders optimum management of mutation carriers. We estimate penetrance for symptomatic tumours and elucidate genotype–phenotype correlations in a large cohort of SDHB/SDHC/SDHD mutation carriers.MethodsA retrospective survey of 1832 individuals referred for genetic testing due to a personal or family history of phaeochromocytoma/paraganglioma. 876 patients (401 previously reported) had a germline mutation in SDHB/SDHC/SDHD (n=673/43/160). Tumour risks were correlated with in silico structural prediction analyses.ResultsTumour risks analysis provided novel penetrance estimates and genotype–phenotype correlations. In addition to tumour type susceptibility differences for individual genes, we confirmed that the SDHD:p.Pro81Leu mutation has a distinct phenotype and identified increased age-related tumour risks with highly destabilising SDHB missense mutations. By Kaplan-Meier analysis, the penetrance (cumulative risk of clinically apparent tumours) in SDHB and (paternally inherited) SDHD mutation-positive non-probands (n=371/67 with detailed clinical information) by age 60 years was 21.8% (95% CI 15.2% to 27.9%) and 43.2% (95% CI 25.4% to 56.7%), respectively. Risk of malignant disease at age 60 years in non-proband SDHB mutation carriers was 4.2%(95% CI 1.1% to 7.2%). With retrospective cohort analysis to adjust for ascertainment, cumulative tumour risks for SDHB mutation carriers at ages 60 years and 80 years were 23.9% (95% CI 20.9% to 27.4%) and 30.6% (95% CI 26.8% to 34.7%).ConclusionsOverall risks of clinically apparent tumours for SDHB mutation carriers are substantially lower than initially estimated and will improve counselling of affected families. Specific genotype–tumour risk associations provides a basis for novel investigative strategies into succinate dehydrogenase-related mechanisms of tumourigenesis and the development of personalised management for SDHB/SDHC/SDHD mutation carriers.

scholarly journals Nephrogenic Syndrome of Inappropriate Antidiuresis

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
D. Morin ◽  
J. Tenenbaum ◽  
B. Ranchin ◽  
T. Durroux
Keyword(s):  
Phenotypic Variability ◽  
Receptor Gene ◽  
Hormone Secretion ◽  
Fluid Restriction ◽  
Missense Mutations ◽  
Loss Of Function ◽  
Vasopressin V2 Receptor ◽  
V2 Receptor ◽  
V2 Receptor Gene ◽  
Inappropriate Antidiuresis

Mutations in the vasopressin V2 receptor gene are responsible for two human tubular disorders: X-linked congenital nephrogenic diabetes insipidus, due to a loss of function of the mutant V2 receptor, and the nephrogenic syndrome of inappropriate antidiuresis, due to a constitutive activation of the mutant V2 receptor. This latter recently described disease may be diagnosed from infancy to adulthood, as some carriers remain asymptomatic for many years. Symptomatic children, however, typically present with clinical and biological features suggesting inappropriate antidiuretic hormone secretion with severe hyponatremia and high urine osmolality, but a low plasma arginine vasopressin level. To date, only two missense mutations in the vasopressin V2 receptor gene have been found in the reported patients. The pathophysiology of the disease requires fuller elucidation as the phenotypic variability observed in patients bearing the same mutations remains unexplained. The treatment is mainly preventive with fluid restriction, but urea may also be proposed.

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