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"Nürnberg, Peter"
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The nexin-dynein regulatory complex subunit DRC1 is essential for motile cilia function in algae and humans
Heymut Omran, Mary Porter and colleagues identify the nexin link–dynein regulatory complex subunit DRC1 from
Chlamydomonas
and show that mutations in the human DRC1 homolog
CCDC164
cause primary ciliary dyskinesia. Their analyses show that loss of DRC1 results in distinct axonemal defects and altered ciliary beat patterns.
Primary ciliary dyskinesia (PCD) is characterized by dysfunction of respiratory cilia and sperm flagella and random determination of visceral asymmetry. Here, we identify the DRC1 subunit of the nexin-dynein regulatory complex (N-DRC), an axonemal structure critical for the regulation of dynein motors, and show that mutations in the gene encoding DRC1,
CCDC164
, are involved in PCD pathogenesis. Loss-of-function mutations disrupting DRC1 result in severe defects in assembly of the N-DRC structure and defective ciliary movement in
Chlamydomonas reinhardtii
and humans. Our results highlight a role for N-DRC integrity in regulating ciliary beating and provide the first direct evidence that mutations in DRC genes cause human disease.
Journal Article
Chromothripsis followed by circular recombination drives oncogene amplification in human cancer
The mechanisms behind the evolution of complex genomic amplifications in cancer have remained largely unclear. Using whole-genome sequencing data of the pediatric tumor neuroblastoma, we here identified a type of amplification, termed ‘seismic amplification’, that is characterized by multiple rearrangements and discontinuous copy number levels. Overall, seismic amplifications occurred in 9.9% (274 of 2,756) of cases across 38 cancer types, and were associated with massively increased copy numbers and elevated oncogene expression. Reconstruction of the development of seismic amplification showed a stepwise evolution, starting with a chromothripsis event, followed by formation of circular extrachromosomal DNA that subsequently underwent repetitive rounds of circular recombination. The resulting amplicons persisted as extrachromosomal DNA circles or had reintegrated into the genome in overt tumors. Together, our data indicate that the sequential occurrence of chromothripsis and circular recombination drives oncogene amplification and overexpression in a substantial fraction of human malignancies.
Seismic amplifications arise from several cycles of circular recombination of circular extrachromosomal DNA formed as a result of chromothripsis. The process provides a mechanism for oncogene amplification in a number of different human tumor types.
Journal Article
Mutations in FAM134B, encoding a newly identified Golgi protein, cause severe sensory and autonomic neuropathy
Ingo Kurth and Christian Hübner report the identification of loss-of-function mutations in
FAM134B
, which encodes a novel
cis
-Golgi protein, in hereditary sensory and autonomic neuropathy type II.
Hereditary sensory and autonomic neuropathy type II (HSAN II) leads to severe mutilations because of impaired nociception and autonomic dysfunction. Here we show that loss-of-function mutations in
FAM134B
, encoding a newly identified
cis
-Golgi protein, cause HSAN II. Fam134b knockdown results in structural alterations of the
cis
-Golgi compartment and induces apoptosis in some primary dorsal root ganglion neurons. This implicates FAM134B as critical in long-term survival of nociceptive and autonomic ganglion neurons.
Journal Article
Long‐lived macrophage reprogramming drives spike protein‐mediated inflammasome activation in COVID‐19
Innate immunity triggers responsible for viral control or hyperinflammation in COVID‐19 are largely unknown. Here we show that the SARS‐CoV‐2 spike protein (S‐protein) primes inflammasome formation and release of mature interleukin‐1β (IL‐1β) in macrophages derived from COVID‐19 patients but not in macrophages from healthy SARS‐CoV‐2 naïve individuals. Furthermore, longitudinal analyses reveal robust S‐protein‐driven inflammasome activation in macrophages isolated from convalescent COVID‐19 patients, which correlates with distinct epigenetic and gene expression signatures suggesting innate immune memory after recovery from COVID‐19. Importantly, we show that S‐protein‐driven IL‐1β secretion from patient‐derived macrophages requires non‐specific monocyte pre‐activation
in vivo
to trigger NLRP3‐inflammasome signaling. Our findings reveal that SARS‐CoV‐2 infection causes profound and long‐lived reprogramming of macrophages resulting in augmented immunogenicity of the SARS‐CoV‐2 S‐protein, a major vaccine antigen and potent driver of adaptive and innate immune signaling.
SYNOPSIS
SARS‐CoV‐2 infection leads to hyperinflammatory syndromes in a subset of patients. We show that human primary macrophages require genome‐wide transcriptional modifications for pro‐inflammatory signaling upon stimulation with the SARS‐CoV‐2 surface glycoprotein (S‐protein).
The SARS‐CoV‐2 spike protein drives NRLP3 inflammasome activation in COVID‐19 patient derived macrophages.
Macrophages from SARS‐CoV‐2 naïve individuals fail to process and subsequently secrete IL‐1β upon stimulation with the S‐protein.
The S‐protein is a pathogen‐associated molecular pattern (PAMP) requiring macrophage pre‐activation for NLRP3 inflammasome formation.
Inflammasome activation and IL‐1β signaling represent attractive targets for pharmacological interventions in severe COVID‐19.
Graphical Abstract
SARS‐CoV‐2 infection leads to hyperinflammatory syndromes in a subset of patients. We show that human primary macrophages require genome‐wide transcriptional modifications for pro‐inflammatory signaling upon stimulation with the SARS‐CoV‐2 surface glycoprotein (S‐protein).
Journal Article
Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency
Adrian Clark and colleagues report mutations in the
NNT
gene encoding nicotinamide nucleotide transhydrogenase in familial glucocorticoid deficiency (FGD).
Using targeted exome sequencing, we identified mutations in
NNT
, an antioxidant defense gene, in individuals with familial glucocorticoid deficiency. In mice with
Nnt
loss, higher levels of adrenocortical cell apoptosis and impaired glucocorticoid production were observed.
NNT
knockdown in a human adrenocortical cell line resulted in impaired redox potential and increased reactive oxygen species (ROS) levels. Our results suggest that NNT may have a role in ROS detoxification in human adrenal glands.
Journal Article
Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia
Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in
BTG1
(2 patients) and homozygous deletions affecting
CDKN2A/B
(3 patients) that developed during treatment, as well as a mutation in
BRAF
and a high-level focal amplification of
CD274
(
PD-L1
) that might pinpoint molecular aberrations offering structures for further therapeutic interventions.
BCL2-inhibitor venetoclax is used to treat relapsed/refractory chronic lymphocytic leukemia (CLL). Here, the authors show the clonal dynamics towards venetoclax resistance by performing whole-exome sequencing of 8 CLL patients undergoing venetoclax treatment.
Journal Article
Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome
Richard Lifton, Véronique Frémeaux-Bacchi and colleagues report that recessive mutations in
DGKE
cause atypical hemolytic-uremic syndrome with an early age of onset progressing to chronic kidney disease. The authors propose that loss of DGKE results in a prothrombotic state that underlies disease pathogenesis.
Pathologic thrombosis is a major cause of mortality. Hemolytic-uremic syndrome (HUS) features episodes of small-vessel thrombosis resulting in microangiopathic hemolytic anemia, thrombocytopenia and renal failure
1
. Atypical HUS (aHUS) can result from genetic or autoimmune factors
2
that lead to pathologic complement cascade activation
3
. Using exome sequencing, we identified recessive mutations in
DGKE
(encoding diacylglycerol kinase ɛ) that co-segregated with aHUS in nine unrelated kindreds, defining a distinctive Mendelian disease. Affected individuals present with aHUS before age 1 year, have persistent hypertension, hematuria and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age. DGKE is found in endothelium, platelets and podocytes. Arachidonic acid–containing diacylglycerols (DAG) activate protein kinase C (PKC), which promotes thrombosis, and DGKE normally inactivates DAG signaling. We infer that loss of
DGKE
function results in a prothrombotic state. These findings identify a new mechanism of pathologic thrombosis and kidney failure and have immediate implications for treating individuals with aHUS.
Journal Article
Mutational dynamics between primary and relapse neuroblastomas
Alexander Schramm, Johannes Schulte and colleagues characterize 16 paired samples from patients with neuroblastoma at diagnosis and relapse using whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis. Their data show the frequency, identity and evolution of genetic alterations in neuroblastoma.
Neuroblastoma is a malignancy of the developing sympathetic nervous system that is often lethal when relapse occurs. We here used whole-exome sequencing, mRNA expression profiling, array CGH and DNA methylation analysis to characterize 16 paired samples at diagnosis and relapse from individuals with neuroblastoma. The mutational burden significantly increased in relapsing tumors, accompanied by altered mutational signatures and reduced subclonal heterogeneity. Global allele frequencies at relapse indicated clonal mutation selection during disease progression. Promoter methylation patterns were consistent over disease course and were patient specific. Recurrent alterations at relapse included mutations in the putative
CHD5
neuroblastoma tumor suppressor, chromosome 9p losses,
DOCK8
mutations, inactivating mutations in
PTPN14
and a relapse-specific activity pattern for the PTPN14 target YAP. Recurrent new mutations in
HRAS
,
KRAS
and genes mediating cell-cell interaction in 13 of 16 relapse tumors indicate disturbances in signaling pathways mediating mesenchymal transition. Our data shed light on genetic alteration frequency, identity and evolution in neuroblastoma.
Journal Article
Impaired Epidermal Ceramide Synthesis Causes Autosomal Recessive Congenital Ichthyosis and Reveals the Importance of Ceramide Acyl Chain Length
The barrier function of the human epidermis is supposed to be governed by lipid composition and organization in the stratum corneum. Disorders of keratinization, namely ichthyoses, are typically associated with disturbed barrier activity. Using autozygosity mapping and exome sequencing, we have identified a homozygous missense mutation in CERS3 in patients with congenital ichthyosis characterized by collodion membranes at birth, generalized scaling of the skin, and mild erythroderma. We demonstrate that the mutation inactivates ceramide synthase 3 (CerS3), which is synthesized in skin and testis, in an assay of N-acylation with C26-CoA, both in patient keratinocytes and using recombinant mutant proteins. Moreover, we show a specific loss of ceramides with very long acyl chains from C26 up to C34 in terminally differentiating patient keratinocytes, which is in line with findings from a recent CerS3-deficient mouse model. Analysis of reconstructed patient skin reveals disturbance of epidermal differentiation with an earlier maturation and an impairment of epidermal barrier function. Our findings demonstrate that synthesis of very long chain ceramides by CerS3 is a crucial early step for the skin barrier formation and link disorders presenting with congenital ichthyosis to defects in sphingolipid metabolism and the epidermal lipid architecture.
Journal Article