Whole exome sequencing in family trios reveals<i>de novo</i>mutations in<i>PURA</i>as a cause of severe neurodevelopmental delay and learning disability

Hunt, David; Leventer, Richard J.; Simons, Cas; Taft, Ryan J.; Swoboda, Kathryn J.; Gawne-Cain, M. L.; Magee, Alex; Turnpenny, Perter D.; Baralle, Diana

doi:10.1136/jmedgenet-2014-102798

Cited by 85 publications

(135 citation statements)

References 39 publications

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“…In previous studies, the transition of dendritic protein MAP2 is thought to be Purα-dependent, Hokkanen's work also found the changes of this protein's expression and distribution. Same as Khalili's work, they also found that the PURA knock-out mice developed a continuous tremor at the age of 2 weeks and this symptom continued throughout lifetime; this observation is consistent with Khalili's report, it indicates that disruption the endogenous level of Purα expression would be associated with the onset of epilepsy, this phenomenon is also confirmed by other researches related to the changes of Purα [19,29], about this we will discuss later in the review.…”

Section: Postnatal Brain Development Was Affected When Purα Has Been supporting

confidence: 76%

“…Another recently discovered neurodegenerative disorder is Fragile X-associated tremor/ataxia syndrome [15], the adult carriers of permutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 [16] gene [17,18] would be affected. In addition, another neuronal developmental disorder linked with Purα is 5q31.3 Microdeletion Syndrome reported by Lalani et al [19] and Hunt et al [20]. For more detailed information about Purα please refer to the review written by Johnson EM [5,21], White MK [22] and Chai J et al [40].…”

Section: Introductionmentioning

confidence: 99%

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The role of Purα in neuronal development, the relationship between Purα and epilepsy in the current researches

et al. 2017

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Abstract. As a ubiquitous protein in the body, Purα has been considered to possess multiple regulatory functions from DNA replication and transcription to RNA transport and translation. The recent studies have proved that Purα protein played a vital role in neuronal development with the solid and abundant evidence both in transgenic mice and human genetic DNA analysis. The Purα knocked out mice models have been successfully established in two independent research groups and their results demonstrated that lack of Purα alters postnatal brain development. Mice lacking of Purα display decreased neurogenesis and impaired neuronal development. In the mouse brain, the expression level of Purα seems to be regulated with brain development. It starts to express Purα after birth and quickly reach to highest level in the third week. The recent studies also have proved that some neurodegenerative disease also linked with Purα, such as Fragile X-associated tremor/ataxia syndrome. rCGG-mediated neuronal toxicity could be modulated by heterogeneous nuclear ribonucleoprotei n A2/B1 and Purα, which is rCGG-repeat-binding proteins. The 5q31.3 microdeletion syndrome is another disorders that is associated with the mutation of Purα gene, it has been demonstrated that all the symptoms such as the neurocognitive impairment, neurodevelopmental delay and learning disability are caused by the mutation of Purα gene. In this mini review, we will retrospectively review the current progress of Purα in neuronal development and try to figure out the connections between these observed phenomena and the biological function of Purα.

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Section: Postnatal Brain Development Was Affected When Purα Has Been supporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

The role of Purα in neuronal development, the relationship between Purα and epilepsy in the current researches

et al. 2017

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“…Three genes in our epilepsy cohort (COQ4, DNM1, and PURA), accounting for 14% (3/21) of all novel genetic etiologies identified in patients with epilepsy, were subsequently confirmed in independent publications. 16,[33][34][35][36] Although it is difficult to assess to what extent this frequency is higher than would be expected by chance, we feel reassured by the fact that approximately 15% of all genes that were reported as potential novel disease genes received subsequent independent confirmation without knowledge of our prior report. This number may provide a baseline for future studies examining the role of diagnostic novel gene reporting.…”

Section: Validation Of Novel Genetic Etiologiesmentioning

confidence: 80%

“…Of the 119 positive/likely positive cases, 105 (88.2%) patients were found to have pathogenic/likely pathogenic mutations in previously characterized disease genes ( 35,36 after the clinical DES report was issued. The authors of these publications were unaware of our reports, and our patients were not included in the respective publications.…”

Section: Characterization Of Molecular Findingsmentioning

confidence: 99%

Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy

Helbig

Hagman

Shinde

et al. 2016

Genetics in Medicine

306

247

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Purpose:To assess the yield of diagnostic exome sequencing (DES) and to characterize the molecular findings in characterized and novel disease genes in patients with epilepsy. Methods:In an unselected sample of 1,131 patients referred for DES, overall results were compared between patients with and without epilepsy. DES results were examined based on age of onset and epilepsy diagnosis.Results: Positive/likely positive results were identified in 112/293 (38.2%) epilepsy patients compared with 210/732 (28.7%) patients without epilepsy (P = 0.004). The diagnostic yield in characterized disease genes among patients with epilepsy was 33.4% (105/314). KCNQ2, MECP2, FOXG1, IQSEC2, KMT2A, and STXBP1 were most commonly affected by de novo alterations. Patients with epileptic encephalopathies had the highest rate of positive findings (43.4%).A likely positive novel genetic etiology was proposed in 14/200 (7%) patients with epilepsy; this frequency was highest in patients with epileptic encephalopathies (17%). Three genes (COQ4, DNM1, and PURA) were initially reported as likely positive novel disease genes and were subsequently corroborated in independent peer-reviewed publications.Conclusion: DES with analysis and interpretation of both characterized and novel genetic etiologies is a useful diagnostic tool in epilepsy, particularly in severe early-onset epilepsy. The reporting on novel genetic etiologies may further increase the diagnostic yield.

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“…Another recently discovered neurodegenerative disorder is fragile X-associated tremor/ataxia syndrome [15], the adult carriers of premutation alleles (55 to 200 CGG repeats) of the fragile X mental retardation 1 [16] gene [17,18] would be affected. In addition, another neuronal developmental disorder linked with Purα is 5q31.3 Microdeletion Syndrome reported by Lalani et al [19] and Hunt et al [20]. For more detailed information about Purα please refer to the review written by Johnson [5,21], White [22] and Chai et al [23].…”

Section: Introductionmentioning

confidence: 99%

The Role of Purα in Neuronal Development, the Progress in the Current Researches

Yuan¹,

Ping²,

Guo³

et al. 2016

J Neurol Neurosci

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As a ubiquitous protein in the body, Purα has been considered to possess multiple regulatory functions from DNA replication and transcription to RNA transport and translation. The recent studies have proved that Purα protein played a vital role in neuronal development with the solid and abundant evidence both in transgenic mice and human genetic DNA analysis. The Purα knocked out mice models have been successfully established in two independent research groups and their results demonstrated that lack of Purα alters postnatal brain development. Mice lacking of Purα display decreased neurogenesis and impaired neuronal development. In the mouse brain, the expression level of Purα seems to be regulated with brain development. It starts to express Purα after birth and quickly reach to highest level in the third week. The recent studies also have proved that some neurodegenerative disease also linked with Purα, such as fragile X-associated tremor/ataxia syndrome. rCGG-mediated neuronal toxicity could be modulated by heterogeneous nuclear ribonucleoprotein A2/B1 and Purα, which is rCGG-repeat-binding proteins. The 5q31.3 Microdeletion Syndrome is another disorder that is associated with the mutation of Purα gene, it has been demonstrated that all the symptoms such as the neurocognitive impairment, neurodevelopmental delay and learning disability are caused by the mutation of Purα gene. In this mini review, we will retrospectively review the current progress of Purα in neuronal development and try to figure out the connections between these observed phenomena and the biological function of Purα.

show abstract

Whole exome sequencing in family trios revealsde novomutations inPURAas a cause of severe neurodevelopmental delay and learning disability

Cited by 85 publications

References 39 publications

The role of Purα in neuronal development, the relationship between Purα and epilepsy in the current researches

The role of Purα in neuronal development, the relationship between Purα and epilepsy in the current researches

Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy

The Role of Purα in Neuronal Development, the Progress in the Current Researches

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