Novel calcineurin A (PPP3CA) variant associated with epilepsy, constitutive enzyme activation and downregulation of protein expression

Rydzanicz, Małgorzata; Wachowska, Malgorzata; Cook, Erik C.; Lisowski, Paweł; Kuzniewska, Bozena; Sztefko, Krystyna; Diecke, Sebastian; Prigione, Alessandro; Szczałuba, Krzysztof; Szybińska, Aleksandra; Koppolu, Agnieszka; Pienkowski, Victor Murcia; Kosińska, Joanna; Wiweger, Małgorzata; Kostrzewa, Grażyna; Brzozowska, Małgorzata; Domańska-Pakieła, Dorota; Jurkiewicz, Elżbieta; Stawiński, Piotr; Gromadka, Agnieszka; Zielenkiewicz, Piotr; Demkow, Urszula; Dziembowska, Magdalena; Kuźnicki, Jacek; Creamer, T.; Płoski, Rafał

doi:10.1038/s41431-018-0254-8

Cited by 33 publications

(28 citation statements)

References 26 publications

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“…WES was performed on the proband DNA using SureSelect Human All Exon v5 (16 patients) or v7 (two patients) (Agilent Technologies, Palo Alto, CA, USA) according to the manufacturer's instructions. The libraries were paired-end sequenced (2 × 100 bp) on the HiSeq 1500 (Illumina, San Diego, CA, USA) in Rapid Run mode and analyzed as previously described [13].…”

Section: Genetic Analysismentioning

confidence: 99%

Rapid Whole-Exome Sequencing as a Diagnostic Tool in a Neonatal/Pediatric Intensive Care Unit

Śmigiel

Biela

Szmyd³

et al. 2020

JCM

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Genetic disorders are the leading cause of infant morbidity and mortality. Due to the large number of genetic diseases, molecular and phenotype heterogeneity and often severe course, these diseases remain undiagnosed. In infants with a suspected acute monogenic disease, rapid whole-exome sequencing (R-WES) can be successfully performed. R-WES (singletons) was performed in 18 unrelated infants with a severe and/or progressing disease with the suspicion of genetic origin hospitalized in an Intensive Care Unit (ICU). Blood samples were also collected from the parents. The results from the R-WES were available after 5-14 days. A conclusive genetic diagnosis was obtained in 13 children, corresponding to an overall diagnostic yield of 72.2%. For nine patients, R-WES was used as a first-tier test. Eight patients were diagnosed with inborn errors of metabolism, mainly mitochondrial diseases. In two patients, the disease was possibly caused by variants in genes which so far have not been associated with human disease (NARS1 and DCAF5). R-WES proved to be an effective diagnostic tool for critically ill infants in ICUs suspected of having a genetic disorder. It also should be considered as a first-tier test after precise clinical description. The quickly obtained diagnosis impacts patient’s medical management, and families can receive genetic counseling.

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Section: Genetic Analysismentioning

confidence: 99%

Rapid Whole-Exome Sequencing as a Diagnostic Tool in a Neonatal/Pediatric Intensive Care Unit

Śmigiel

Biela

Szmyd³

et al. 2020

JCM

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“…According to previous reports, most of the documented mutations in PPP3CA are missense mutations (Fig. 2), resulting in the gain or loss of function [1][2][3]6]. Among them, only missense located at the upstream of AID domain displayed a loss-of-function effect and presented IECEE1 phenotypes in patients.…”

Section: Genetic Analysismentioning

confidence: 86%

“…To date, 14 mutations from 6 papers have been reported [1][2][3][4][5][6], including 8 missenses, 2 nonsenses, 1 splicing mutation, and 2 small insertions associated with IECEE1. Here, we reported our experience in the diagnosis of a 2-year-old Chinese IECEE1 patient, using the clinical and genetic examinations.…”

Section: Introductionmentioning

confidence: 99%

Clinical and Genetic Study on a Chinese Patient with Infantile Onset Epileptic Encephalopathy carrying a PPP3CA Null Variant: a case report

Yang

Shen²,

Kang

et al. 2020

BMC Pediatr

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Background: PPP3CA gene encodes the catalytic subunit A of a calcium-dependent protein phosphatase called calcineurin. However, two distinct mechanisms in PPP3CA deficiency would cause two clinically different diseases. Gain-of-function mutations in the autoinhibitory domain at the C-terminus would cause ACCIID that stands for arthrogryposis, cleft palate, craniosynostosis and impaired intellectual development. While loss-of-function mutations in PPP3CA would cause infantile or early childhood onset epileptic encephalopathy1, named as IECEE1. IECEE1 is a severe epileptic neurodevelopmental disorder and mainly characterized by psychomotor delay. Here, we report a Chinese patient who was clinically and genetically diagnosed as IECEE1. We also extensively analyzed electroencephalogram (EEG) features of the patient in this study. Case presentation: A 2-year-old Chinese patient who had recurrent polymorphic seizures was clinically and genetically diagnosed as IECEE1. A frameshift variant c.1283insC (p.T429NfsX22) was identified in this case. Multiple types of abnormal features were observed in the EEG, comparing with the previous reports. Conclusions: These findings could expand the spectrum of PPP3CA mutations and might also support the diagnosis and further study of IECEE1.

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“…Libraries were prepared according to manufacturers' instructions and paired‐end sequenced (2 × 100 bp) on HiSeq 1500 (Illumina, San Diego, CA, USA). Bioinformatics analysis of NGS data was performed as described …”

Section: Methodsmentioning

confidence: 99%

A study in a Polish ataxia cohort indicates genetic heterogeneity and points to MTCL1 as a novel candidate gene

et al. 2019

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Inherited ataxias are a group of highly heterogeneous, complex neurological disorders representing a significant diagnostic challenge in clinical practice. We performed a next-generation sequencing (NGS) analysis in 10 index cases with unexplained progressive cerebellar ataxia of suspected autosomal recessive inheritance. A definite molecular diagnosis was obtained in 5/10 families and included the following diseases: autosomal recessive spastic ataxia of Charlevoix-Saguenay, POLR3B-related hypomyelinating leukodystrophy, primary coenzyme Q10 deficiency type 4, Niemann-Pick disease type C1 and SYNE1-related ataxia. In addition, we found a novel homozygous MTCL1 loss of function variant p.(Lys407fs) in a 23-year-old patient with slowly progressive cerebellar ataxia, mild intellectual disability, seizures in childhood and episodic pain in the lower limbs. The identified variant is predicted to truncate the protein after first 444 of 1586 amino acids. MTCL1 encodes a microtubule-associated protein highly expressed in cerebellar Purkinje cells; its knockout in a mouse model causes ataxia. We propose MTCL1 as a candidate gene for autosomal recessive cerebellar ataxia in humans. In addition, our study confirms the high diagnostic yield of NGS in early-onset cerebellar ataxias, with at least 50% detection rate in our ataxia cohort.

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Novel calcineurin A (PPP3CA) variant associated with epilepsy, constitutive enzyme activation and downregulation of protein expression

Cited by 33 publications

References 26 publications

Rapid Whole-Exome Sequencing as a Diagnostic Tool in a Neonatal/Pediatric Intensive Care Unit

Rapid Whole-Exome Sequencing as a Diagnostic Tool in a Neonatal/Pediatric Intensive Care Unit

Clinical and Genetic Study on a Chinese Patient with Infantile Onset Epileptic Encephalopathy carrying a PPP3CA Null Variant: a case report

A study in a Polish ataxia cohort indicates genetic heterogeneity and points to MTCL1 as a novel candidate gene

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