SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation

SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients’ primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis

Verkliga styrningsutmaningar i megaprojekt

Syfte: Syftet med studien har varit att undersöka de motiv, erfarenheter och reflektioner som beställare av megaprojekt, i det svenska fallet Trafikverket, själva upplever i sin styrning samt sprida kunskaper kring de praktiska utmaningar som framkommer och på så sätt stimulera verksamhetsutveckling bland beställare av megaprojekt. Teori: Det finns tre kritiska perspektiv mot den traditionella projektstyrningslitteraturen som belyser måltriangelns bristande relevans i megaprojekt, den institutionella miljöns påverkan på styrningen samt argument för att megaprojekt bör studeras som temporära organisationer Metod: I studien har en kvalitativ och abduktiv ansats valts ut för insamling av empiri genom semistrukturerade intervjuer med projektledare, controllers, stabschefer och projektchefer. Intervjufrågorna formats utifrån den traditionella projektstyrningslitteraturen. Det empiriska resultatet som erhållits genom intervjuer har även kompletterats genom en kvalitativ dokumentanalys. Resultat: Studien visar att det används olika instrument, tekniker och modeller för att planera och styra megaprojekt. Dessa kan antas vara varianter av de som beskrivits av den traditionella projektstyrninglitteraturen som framgångsmodeller vad gäller styrning. De utmaningar och problem som beställarna står inför i svenska megaprojekt har dock många gånger lämnats utanför samma litteratur, vilket innebär att de aktörer vi studerade fick anpassa modellerna utefter lokala förutsättningar och utmaningar. Många av de utmaningar som identifierats i studien är också komplexa och svåra att generalisera eller att paketera i en viss förespråkad modell

A new case of Bainbridge-Ropers syndrome (BRPS): delineating the phenotype and review of literature

Background: Bainbridge-Ropers syndrome (BRPS) is characterized by failure to thrive, global developmental delay, feeding problems, hypotonia, profound speech delays, and intellectual disability and dysmorphic features. It is an autosomal dominant condition caused by heterozygous mutations in the ASXL3 gene (OMIM #615115) on chromosome 18q12. As per the literature available, only 39 cases including the current patient were reported with BRPS across the globe. Case presentation: A 4-year-old girl with confirmed BRPS. She had the characteristic features of the disease including psychomotor delay, hypotonia, profound speech impairment, neonatal feeding difficulties, postnatal, and dysmorphic features. The array CGH and whole exome sequencing were negative, but the whole genome sequencing detected a novel heterozygous de novo insertion in the ASXL3 gene c.3592_3593insGAT; p.Leu1198X. Conclusion: With the advent of whole exome/genome sequencing we would expect to diagnose more cases of BRPS from different ethnic populations. Further clinical and functional studies are needed to delineate the long-term course of the disease and to elaborate on the exact role of the ASXL3 gene in brain development. [JBCGenetics 2019; 2(1.000): 65-69

Epileptic encephalopathy caused by biallelic mutation in PPM1D: a case report

Background: PPM1D gene encodes for metal-dependent protein phosphatase. Its function includes the inhibition of some tumor suppressor genes, DNA damage response, and cell cycle control. Germline heterozygous de novo mutations in this gene were reported to cause intellectual disability and hypotonia. Case Presentation: We report a 40-month-old girl with an intractable seizure disorder, microcephaly, and global developmental delay. She had frequent epileptiform discharges on electroencephalography. Molecular investigations showed a homozygous truncating mutation in the PPM1D gene. Both parents were healthy heterozygous carriers. Conclusion: This is the first time in the literature to describe a homozygous biallelic mutation in the PPM1D gene, which resulted in epileptic encephalopathy, microcephaly, and global developmental delay. PPM1D mutations could be inherited as autosomal recessive with asymptomatic heterozygote carriers. [JBCGenetics 2018; 1(1.000): 47-50

Methionine adenosyltransferase I/III deficiency: beyond the central nervous system manifestations

Marwan Nashabat,1 Sultan Al-Khenaizan,2 Majid Alfadhel1 1King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, Division of Genetics, Department of Pediatrics, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia; 2Department of Dermatology, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia Abstract: Methionine adenosyltransferase (MAT) I/III deficiency (OMIM # 250850) is caused by a mutation in MAT1A, which encodes the two hepatic MAT isozymes I and III. With the implementation of newborn screening program to discover hypermethioninemia due to cystathionine beta-synthase deficiency, more cases are being discovered. While the majority of patients are asymptomatic, some might have central nervous system (CNS) and extra-CNS manifestations. Although neurologic manifestations and demyelination have been correlated to MAT deficiency in many reported cases, none of the previous reports focused on extra-CNS manifestations associated with the disease. This is a retrospective chart review for a 40-month-old patient with confirmed diagnosis of MAT deficiency. He was found to have a novel homozygous disease-causing variant in MAT1A (NM_000429.2) c.1081G>T (p.Val361Phe). Interestingly, our patient had an unexplained zinc and iron deficiency in addition to mild speech delay. We reviewed the literature and summarized all the reported extra-CNS manifestations. In conclusion, MAT deficiency patients should be thoroughly investigated to check for CNS and extra-CNS manifestations associated with the disease. Keeping in consideration the challenge of assuming correlation, a scrutinized look at extra-CNS manifestations and their course with time might pave the way to understanding the pathophysiology of the disease and MAT1A function. Keywords: MAT1A, methionine adenosyltransferase, S-adenosyl methionine, central nervous system&nbsp

Numerische Modellierung der Wirbelstromprüfung geschichteter Strukturen aus Aluminium zur quantitativen Bestimmung simulierter Korrosionsschäden an Flugzeugkonstruktionen: Experimentelle Ergebnisse

The potential of theoretic-numerical modelling of practical testing problems is presented by examples of nondestructive testing using the multifrequency eddy current method. Modelling of eddy current testing tasks allows the problem-oriented selection of the probe and the test frequency, thus an optimization of the testing system avoiding the usually costly and time-consuming development and production of specimens and probes. A commercial programme package on the basis of the volume-integral-method was used for the modelling of the test signals. Examples of solutions for the optimization of the test parameters for the detection and evaluation of corrosion defects (weakening of the wall thickness) in multilayer aeroplane constructions (glued aluminium sheets) are demonstrated and compared to measurement results of a testing device with suitable parameters. At present this kind of testing system not state-of-the-art

Pulmonary hypertension and vasculopathy in incontinentia pigmenti: a case report

Abduljabbar Alshenqiti,1 Marwan Nashabat,1 Hissah AlGhoraibi,1 Omar Tamimi,2 Majid Alfadhel1 1Division of Genetics, Department of Pediatrics, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz Uiversity for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs (NGHA), Riyadh, Saudi Arabia; 2Department of Cardiology, King Abdullah International Medical Research Centre, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs (NGHA), Riyadh, Saudi Arabia Abstract: Incontinentia pigmenti (IP; Bloch–Sulzberger syndrome) is a rare, genetic syndrome inherited as an X-linked dominant trait. It primarily affects female infants and is lethal in the majority of males during fetal life. The clinical findings include skin lesions, developmental defects, and defects of the eyes, teeth, skeletal system, and central nervous system. Cardiovascular complications of this disease in general, and pulmonary hypertension in particular, are extremely rare. This report describes the case of a 3-year-old girl with IP complicated by pulmonary arterial hypertension. Extensive cardiology workup done to the patient indicates underlying vasculopathy. This report sheds light on the relationship between IP and pulmonary hypertension, reviews the previously reported cases, and compares them with the reported case. Keywords: incontinentia pigmenti, IKBKG, pulmonary hypertension, vasculopathy, Bloch–Sulzberger syndrome, lines of Blaschko, hyperpigmentatio

The association between IVF and chromosomal abnormalities compared to spontaneous conception

In vitro fertilization (IVF) is a process by which an egg is extracted by needle aspiration and then combined with a sperm so that fertilization can occur outside the body. Genetic defects, such as chromosomal abnormalities, are considered rare among the general population; however, even though their incidence among IVF-conceived children is uncommon, several alarming studies were published on the increased risk of chromosomal abnormalities IVF/intracytoplasmic sperm injection (ICSI)-conceived children compared to universal rates. This study aimed to review the literature and present data to answer whether IVF or ICSI is associated with an increased risk of chromosomal abnormalities inborn after IVF/ICSI treatment compared to spontaneously conceived children. Relevant published scientific articles were searched in the Medline database, using combinations of the following key terms: "IVF", "in vitro fertilization", "ICSI", "intracytoplasmic sperm injection", "natural conception", "spontaneous conception" along with "chromosomal abnormalities", "chromosomal defects", "sex chromosome aneuploidy", and "trisomy". The eligible studies were considered as studies exploring the association of IVF/ICSI with chromosomal abnormalities compared to spontaneous conception. The search included studies published from 1992 to 2018. The results for the association of chromosomal abnormalities and IVF remain unclear. As many studies proved a significant increase in chromosomal abnormalities and syndromes among the IVF population, other studies were contradicting and contributed the abnormalities to several environmental and technical factors. [JBCGenetics 2021; 4(1.000): 42-47