scholarly journals Prenatal phenotype of PNKP-related primary microcephaly associated with variants in the FHA and Phosphatase domain

2021 ◽  
Author(s):  
Sonja Neuser ◽  
Ilona Krey ◽  
Annemarie Schwan ◽  
Tobias Bartolomaeus ◽  
Jan Henje Doering ◽  
...  
Keyword(s):  
Structural Damage ◽  
Pregnancy Termination ◽  
Neurodevelopmental Disorder ◽  
Computational Modelling ◽  
Pathological Examination ◽  
Primary Microcephaly ◽  
Fha Domain ◽  
Phosphatase Domain ◽  
Charcot Marie Tooth Disease ◽  
Clinical Description

Biallelic PNKP variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot-Marie-Tooth disease. To date, only postnatal descriptions exist. We present the first prenatal diagnosis of PNKP-related primary microcephaly. Detailed pathological examination of a male fetus revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities in a sibling fetus. Prenatal trio exome sequencing identified compound-heterozygosity for the PNKP variants c.498G>A, p.[(=),0?] and c.302C>T, p.(Pro101Leu). Segregation confirmed both variants in the sibling fetus. Through RNA analyses, we characterized skipping of exon 4 affecting the PNKP Forkhead-associated (FHA) and Phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the same splice-donor variant c.1029+2T>C in trans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro) and c.151G>C, p.(Val51Leu), respectively). RNA-seq showed complex splicing events for c.1029+2T>C and c.151G>C. Computational modelling and structural analysis revealed significant clustering of missense variants in the FHA domain, with some variants potentially generating structural damage. Our detailed clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modelling, we highlight the mutational complexity and exemplify a framework for variant characterization in this multi-domain protein.

Two new cases of nonepileptic neurodevelopmental disorder due to GRIN2B variants and detailed clinical description of the behavioral phenotype

2021 ◽  
Vol Publish Ahead of Print ◽  
Author(s):  
Paola Sabrina Buonuomo ◽  
Gerarda Mastrogiorgio ◽  
Paolo Alfieri ◽  
Alessandra Terracciano ◽  
Claudia Cesario ◽  
...  
Keyword(s):  
Neurodevelopmental Disorder ◽  
Behavioral Phenotype ◽  
Clinical Description

scholarly journals Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair

2020 ◽  
Vol 48 (12) ◽  
pp. 6672-6684 ◽  
Author(s):  
Ilona Kalasova ◽  
Richard Hailstone ◽  
Janin Bublitz ◽  
Jovel Bogantes ◽  
Winfried Hofmann ◽  
...  
Keyword(s):  
Strand Break ◽  
Single Strand ◽  
Dna Double Strand Breaks ◽  
Fha Domain ◽  
Single Strand Break ◽  
Strand Breaks ◽  
Charcot Marie Tooth Disease ◽  
Single Strand Break Repair ◽  
Primary Determinant ◽  
Break Repair

Abstract Hereditary mutations in polynucleotide kinase-phosphatase (PNKP) result in a spectrum of neurological pathologies ranging from neurodevelopmental dysfunction in microcephaly with early onset seizures (MCSZ) to neurodegeneration in ataxia oculomotor apraxia-4 (AOA4) and Charcot-Marie-Tooth disease (CMT2B2). Consistent with this, PNKP is implicated in the repair of both DNA single-strand breaks (SSBs) and DNA double-strand breaks (DSBs); lesions that can trigger neurodegeneration and neurodevelopmental dysfunction, respectively. Surprisingly, however, we did not detect a significant defect in DSB repair (DSBR) in primary fibroblasts from PNKP patients spanning the spectrum of PNKP-mutated pathologies. In contrast, the rate of SSB repair (SSBR) is markedly reduced. Moreover, we show that the restoration of SSBR in patient fibroblasts collectively requires both the DNA kinase and DNA phosphatase activities of PNKP, and the fork-head associated (FHA) domain that interacts with the SSBR protein, XRCC1. Notably, however, the two enzymatic activities of PNKP appear to affect different aspects of disease pathology, with reduced DNA phosphatase activity correlating with neurodevelopmental dysfunction and reduced DNA kinase activity correlating with neurodegeneration. In summary, these data implicate reduced rates of SSBR, not DSBR, as the source of both neurodevelopmental and neurodegenerative pathology in PNKP-mutated disease, and the extent and nature of this reduction as the primary determinant of disease severity.

scholarly journals NMIHBA results from hypomorphic PRUNE1 variants that lack short-chain exopolyphosphatase activity

2020 ◽  
Author(s):  
Harikiran Nistala ◽  
John Dronzek ◽  
Claudia Gonzaga-Jauregui ◽  
Shek Man Chim ◽  
Saathyaki Rajamani ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Neurodevelopmental Disorder ◽  
Cortical Atrophy ◽  
Global Developmental Delay ◽  
Compound Heterozygous ◽  
Genetic Ablation ◽  
Severe Intellectual Disability ◽  
Disease Biology ◽  
Variant Alleles ◽  
Clinical Description

Abstract Neurodevelopmental disorder with microcephaly, hypotonia and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G > A (p.Arg128Gln), c.520G > T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.

Autosomal Recessive Primary Microcephaly (MCPH): An Update

2017 ◽  
Vol 48 (03) ◽  
pp. 135-142 ◽  
Author(s):  
Deborah Morris-Rosendahl ◽  
Angela Kaindl ◽  
Sami Zaqout
Keyword(s):  
Intellectual Disability ◽  
Head Circumference ◽  
Autosomal Recessive ◽  
Neurodevelopmental Disorder ◽  
Speech Disorder ◽  
Rare Disorder ◽  
Primary Microcephaly ◽  
Expressive Speech ◽  
Autosomal Recessive Primary Microcephaly

AbstractAutosomal recessive primary microcephaly (MCPH; MicroCephaly Primary Hereditary) is a genetically heterogeneous neurodevelopmental disorder characterized by a significantly reduced head circumference present already at birth and intellectual disability. Inconsistent features include hyperactivity, an expressive speech disorder, and epilepsy. Here, we provide a brief overview on this rare disorder pertinent for clinicians.

scholarly journals Deficient Myocardial Organization and Pathological Fibrosis in Fetal Aortic Stenosis—Association of Prenatal Ultrasound with Postmortem Histology

2021 ◽  
Vol 8 (10) ◽  
pp. 121
Author(s):  
Fleur Zwanenburg ◽  
Marco C. DeRuiter ◽  
Lambertus J. Wisse ◽  
Conny J. van Munsteren ◽  
Margot M. Bartelings ◽  
...  
Keyword(s):  
Aortic Stenosis ◽  
Structural Damage ◽  
Fetal Echocardiography ◽  
Pregnancy Termination ◽  
Myocardial Strain ◽  
Left Ventricular ◽  
Myocardial Deformation ◽  
Fetal Ultrasound ◽  
Chamber View ◽  
Potential Biomarker

In fetal aortic stenosis (AS), it remains challenging to predict left ventricular development over the course of pregnancy. Myocardial organization, differentiation and fibrosis could be potential biomarkers relevant for biventricular outcome. We present four cases of fetal AS with varying degrees of severity and associate myocardial deformation on fetal ultrasound with postmortem histopathological characteristics. During routine fetal echocardiography, speckle tracking recordings of the cardiac four-chamber view were performed to assess myocardial strain as parameter for myocardial deformation. After pregnancy termination, postmortem cardiac specimens were examined using immunohistochemical labeling (IHC) of key markers for myocardial organization, differentiation and fibrosis and compared to normal fetal hearts. Two cases with critical AS presented extremely decreased left ventricular (LV) strain on fetal ultrasound. IHC showed overt endocardial fibro-elastosis, which correlated with pathological fibrosis patterns in the myocardium and extremely disturbed cardiomyocyte organization. The LV in severe AS showed mildly reduced myocardial strain and less severe disorganization of the cardiomyocytes. In conclusion, the degree of reduction in myocardial deformation corresponded with high extent to the amount of pathological fibrosis patterns and cardiomyocyte disorganization. Myocardial deformation on fetal ultrasound seems to hold promise as a potential biomarker for left ventricular structural damage in AS.

scholarly journals Detecting structural damage to bridge girders using radar interferometry and computational modelling

2017 ◽  
Vol 24 (10) ◽  
pp. e1985 ◽  
Author(s):  
Maizuar Maizuar ◽  
Lihai Zhang ◽  
Saeed Miramini ◽  
Priyan Mendis ◽  
Russell G. Thompson
Keyword(s):  
Structural Damage ◽  
Computational Modelling ◽  
Radar Interferometry ◽  
Bridge Girders

scholarly journals Birdstrike Analysis on Leading Edge of an Aircraft Wing Using a Smooth Particle Hydrodynamics Bird Model

2010 ◽  
Author(s):  
Vinayak Walvekar ◽  
Chandrashekhar K. Thorbole ◽  
Prasanna Bhonge ◽  
Hamid M. Lankarani
Keyword(s):  
Finite Element ◽  
Structural Damage ◽  
Human Life ◽  
Computational Modelling ◽  
Leading Edge ◽  
Smooth Particle Hydrodynamics ◽  
Nose Radius ◽  
Certification Procedure ◽  
Physical Testing ◽  
Particle Hydrodynamics

With the increase in air travel, the recent occurrences of birdstrikes on aircraft pose a major threat to human life; hence, there is a need to develop aircraft structures with a high resistance to such occurrences. According to the Federal Aviation Regulation (FAR 25.571) on Damage-Tolerance and Fatigue Evaluation of Structure (Amdt. 25-96), an airplane must be capable of successfully completing a flight during which likely structural damage might occur as a result of impact with a four-pound (1.8 kg) bird at sea-level cruise velocity or 0.85 percent of cruise velocity at 8,000 feet (2,400 m). Since the actual physical testing of a birdstrike is expensive, time-consuming, and cumbersome, this paper presents a methodology, based on the use of analytical finite element modeling and analysis, to certify an aircraft for a birdstrike. In actual physical testing for birdstrikes the mass of the bird might not be accurate and hence for certification purpose the computational modelling technique is more accurate and standardizes the certification procedure. The modeling and simulations are carried out as follows: the bird is modeled using the smooth particle hydrodynamics (SPH) technique in the LS-Dyna nonlinear finite element code. To validate this model, birdstrikes are carried out on rigid and deformable plates. The results, including displacement, Von-Mises stresses, forces, impulse, squash time and rise time, are obtained from the simulation, and non-dimensional values are plotted and compared with results from the test data. The detailed CAD geometry of the leading edge of an aircraft is modeled in CATIA V5. Meshing, connections, and material properties are then defined in the Altair Hypermesh 9.0 program. The results obtained from the birdstrike simulations on this leading edge are compared to data from the experiments, and the process is validated. Parametric studies are carried out by designing the aircraft leading edge for different values of nose radius and by assigning appropriate thickness values for leading-edge components and impacting the SPH-modeled bird at different velocities. The methodology and results obtained from simulation can be utilized in the initial design stages as well as for “certification by analysis” of an aircraft for birdstrike requirements as per federal regulations.

Vasospasm in response to repeated subarachnoid hemorrhages in the monkey

1970 ◽  
Vol 33 (4) ◽  
pp. 395-406 ◽  
Author(s):  
Bryce Weir ◽  
Ramon Erasmo ◽  
Jack Miller ◽  
John McIntyre ◽  
David Secord ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Subarachnoid Hemorrhage ◽  
Structural Damage ◽  
Fluid Pressure ◽  
Pressure Rise ◽  
Pathological Examination ◽  
Content Type ◽  
Subarachnoid Hemorrhages ◽  
The Relationship ◽  
Fine Print

✓ This study investigates the relationship between vasospasm and repeated subarachnoid hemorrhages in 18 monkeys. Sixteen received weekly 4 cc injections of autogenous blood into the subfrontal subarachnoid space. The weekly mortality rate for 4 weeks was 6%, 33%, 20%, and 37% respectively. The over-all mortality was 75%. The degree of vasospasm did not correlate with the morbidity and mortality. Vasospasm was limited to the intradural cerebral vessels and was diffuse. It never lasted longer than a few hours, late vasospasm did not occur, and the degree of vasospasm did not alter with repeated occasions of “subarachnoid hemorrhage.” Immediate electrocardiogram abnormalities were related to the height of the cerebrospinal fluid pressure rise following the subarachnoid hemorrhage (injected blood). Pathological examination of the vessels shown to be in spasm was normal. The study suggests that the increased mortality associated with repeated subarachnoid hemorrhage is due to cumulative structural damage rather than a heightened vasospastic response to repeated hemorrhages.

scholarly journals Functional modeling of NMIHBA-causing PRUNE1 variants reveals a requirement for its exopolyphosphatase activity

2020 ◽  
Author(s):  
Harikiran Nistala ◽  
John Dronzek ◽  
Claudia Gonzaga-Jauregui ◽  
Shek Man Chim ◽  
Saathyaki Rajamani ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Neurodevelopmental Disorder ◽  
Cortical Atrophy ◽  
Global Developmental Delay ◽  
Compound Heterozygous ◽  
Genetic Ablation ◽  
Severe Intellectual Disability ◽  
Disease Biology ◽  
Variant Alleles ◽  
Clinical Description

AbstractNeurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G>A (p.Arg128Gln), c.520G>T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.

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