Investigators seeking to identify genetic prognostic markers in a clinical trial to treat acute myeloid leukemia found that minimal residual disease, detected by the presence of mutation in
NPM1,
...provided prognostic information independent of other risk factors.
Although acute myeloid leukemia (AML) is genetically less complex than many other tumors, the condition is molecularly heterogeneous.
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Despite improved understanding of the mutational landscape, treatment decisions, particularly regarding allogeneic stem-cell transplantation, remain guided by cytogenetic analysis, a limited panel of molecular genetic markers, and morphology-based assessment of remission.
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Currently, a predicted risk of relapse of more than 35% is widely considered to warrant stem-cell transplantation during the first remission.
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Patients with high-risk disease undergo stem-cell transplantation if feasible, whereas those with low-risk disease usually do not. However, there is uncertainty about the role of transplantation in patients . . .
Excessive growth of terminal hair around the elbows (hypertrichosis cubiti) has been reported both in isolation and in association with a variable spectrum of associated phenotypic features. We ...identified a cohort of six individuals with hypertrichosis cubiti associated with short stature, intellectual disability, and a distinctive facial appearance, consistent with a diagnosis of Wiedemann-Steiner syndrome (WSS). Utilizing a whole-exome sequencing approach, we identified de novo mutations in MLL in five of the six individuals. MLL encodes a histone methyltransferase that regulates chromatin-mediated transcription through the catalysis of methylation of histone H3K4. Each of the five mutations is predicted to result in premature termination of the protein product. Furthermore, we demonstrate that transcripts arising from the mutant alleles are subject to nonsense-mediated decay. These findings define the genetic basis of WSS, provide additional evidence for the role of haploinsufficency of histone-modification enzymes in multiple-congenital-anomaly syndromes, and further illustrate the importance of the regulation of histone modification in development.
Psoriasis is a common inflammatory skin disease caused by the interplay between multiple genetic and environmental risk factors. This review summarises recent progress in elucidating the genetic ...basis of psoriasis, particularly through large genome-wide association studies. We illustrate the power of genetic analyses for disease stratification. Psoriasis can be stratified by phenotype (common plaque versus rare pustular variants), or by outcome (prognosis, comorbidities, response to treatment); recent progress has been made in delineating the genetic contribution in each of these areas. We also highlight how genetic data can directly inform the development of effective psoriasis treatments.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Whole-genome sequencing (WGS) is becoming widely used in clinical medicine in diagnostic contexts and to inform treatment choice. Here we evaluate the potential of the Oxford Nanopore Technologies ...(ONT) MinION long-read sequencer for routine WGS by sequencing the reference sample NA12878 and the genome of an individual with ataxia-pancytopenia syndrome and severe immune dysregulation. We develop and apply a novel reference panel-free analytical method to infer and then exploit phase information which improves single-nucleotide variant (SNV) calling performance from otherwise modest levels. In the clinical sample, we identify and directly phase two non-synonymous de novo variants in SAMD9L, (OMIM #159550) inferring that they lie on the same paternal haplotype. Whilst consensus SNV-calling error rates from ONT data remain substantially higher than those from short-read methods, we demonstrate the substantial benefits of analytical innovation. Ongoing improvements to base-calling and SNV-calling methodology must continue for nanopore sequencing to establish itself as a primary method for clinical WGS.
Generalized pustular psoriasis (GPP) is a rare and yet potentially lethal clinical variant of psoriasis, characterized by the formation of sterile cutaneous pustules, neutrophilia, fever and features ...of systemic inflammation. We sequenced the exomes of five unrelated individuals diagnosed with GPP. Nonsynonymous, splice-site, insertion, and deletion variants with an estimated population frequency of <0.01 were considered as candidate pathogenic mutations. A homozygous c.338C>T (p.Ser113Leu) missense substitution of IL36RN was identified in two individuals, with a third subject found to be a compound heterozygote for c.338C>T (p.Ser113Leu) and a c.142C>T (p.Arg48Trp) missense substitution. IL36RN (previously known as IL1F5) encodes an IL-1 family receptor antagonist, which opposes the activity of the IL-36A and IL-36G innate cytokines. Homology searches revealed that GPP mutations alter evolutionarily conserved residues. Homozygosity for the c.338C>T (p.Ser113Leu) variant is associated with an elevated proinflammatory response following ex vivo stimulation with IL36A. These findings suggest loss of function of IL36RN as the genetic basis of GPP and implicate innate immune dysregulation in this severe episodic inflammatory disease, thereby highlighting IL-1 signaling as a potential target for therapeutic intervention.
The study of DNA sequence variation has been transformed by recent advances in DNA sequencing technologies. Determination of the functional consequences of sequence variant alleles offers potential ...insight as to how genotype may influence phenotype. Even within protein coding regions of the genome, establishing the consequences of variation on gene and protein function is challenging and requires substantial laboratory investigation. However, a series of bioinformatics tools have been developed to predict whether non-synonymous variants are neutral or disease-causing. In this study we evaluate the performance of nine such methods (SIFT, PolyPhen2, SNPs&GO, PhD-SNP, PANTHER, Mutation Assessor, MutPred, Condel and CAROL) and developed CoVEC (Consensus Variant Effect Classification), a tool that integrates the prediction results from four of these methods. We demonstrate that the CoVEC approach outperforms most individual methods and highlights the benefit of combining results from multiple tools.
•We benchmark 8 SNP effect prediction tools and use them in a consensus strategy.•Dataset of disease-causing SNPs from HGMD and common SNPs from 1000 Genomes Project•PolyPhen2 found to be most sensitive method, SNPs&GO most selective.•Consensus outperforms previous similar efforts and individual tools.•Consensus tool (CoVEC) available via the web or local scripts
Although manganese is an essential trace metal, little is known about its transport and homeostatic regulation. Here we have identified a cohort of patients with a novel autosomal recessive manganese ...transporter defect caused by mutations in SLC39A14. Excessive accumulation of manganese in these patients results in rapidly progressive childhood-onset parkinsonism-dystonia with distinctive brain magnetic resonance imaging appearances and neurodegenerative features on post-mortem examination. We show that mutations in SLC39A14 impair manganese transport in vitro and lead to manganese dyshomeostasis and altered locomotor activity in zebrafish with CRISPR-induced slc39a14 null mutations. Chelation with disodium calcium edetate lowers blood manganese levels in patients and can lead to striking clinical improvement. Our results demonstrate that SLC39A14 functions as a pivotal manganese transporter in vertebrates.
Nephrotic syndrome (NS), the association of gross proteinuria, hypoalbuminaemia, edema, and hyperlipidemia, can be clinically divided into steroid-sensitive (SSNS) and steroid-resistant (SRNS) forms. ...SRNS regularly progresses to end-stage renal failure. By homozygosity mapping and whole exome sequencing, we here identify recessive mutations in Crumbs homolog 2 (CRB2) in four different families affected by SRNS. Previously, we established a requirement for zebrafish crb2b, a conserved regulator of epithelial polarity, in podocyte morphogenesis. By characterization of a loss-of-function mutation in zebrafish crb2b, we now show that zebrafish crb2b is required for podocyte foot process arborization, slit diaphragm formation, and proper nephrin trafficking. Furthermore, by complementation experiments in zebrafish, we demonstrate that CRB2 mutations result in loss of function and therefore constitute causative mutations leading to NS in humans. These results implicate defects in podocyte apico-basal polarity in the pathogenesis of NS.
Elucidating genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Here we show that protein-truncating mutations in the tight ...junction protein 2 gene (TJP2) cause failure of protein localization and disruption of tight-junction structure, leading to severe cholestatic liver disease. These findings contrast with those in the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Adenosine diphosphate (ADP)‐ribosylation is a post‐translational protein modification implicated in the regulation of a range of cellular processes. A family of proteins that catalyse ...ADP‐ribosylation reactions are the poly(ADP‐ribose) (PAR) polymerases (PARPs). PARPs covalently attach an ADP‐ribose nucleotide to target proteins and some PARP family members can subsequently add additional ADP‐ribose units to generate a PAR chain. The hydrolysis of PAR chains is catalysed by PAR glycohydrolase (PARG). PARG is unable to cleave the mono(ADP‐ribose) unit directly linked to the protein and although the enzymatic activity that catalyses this reaction has been detected in mammalian cell extracts, the protein(s) responsible remain unknown. Here, we report the homozygous mutation of the c6orf130 gene in patients with severe neurodegeneration, and identify C6orf130 as a PARP‐interacting protein that removes mono(ADP‐ribosyl)ation on glutamate amino acid residues in PARP‐modified proteins. X‐ray structures and biochemical analysis of C6orf130 suggest a mechanism of catalytic reversal involving a transient C6orf130 lysyl‐(ADP‐ribose) intermediate. Furthermore, depletion of C6orf130 protein in cells leads to proliferation and DNA repair defects. Collectively, our data suggest that C6orf130 enzymatic activity has a role in the turnover and recycling of protein ADP‐ribosylation, and we have implicated the importance of this protein in supporting normal cellular function in humans.
Crystal structure and biochemical data reveal a gene mutated in patients with severe neurodegeneration to encode an elusive enzyme for removing ADP‐ribose from proteins.
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