<scp>Jansen‐de Vries</scp> syndrome: Expansion of the <scp><i>PPM1D</i></scp> clinical and phenotypic spectrum in 34 families

Wojcik, Monica H.; Srivastava, Siddharth; Agrawal, Pankaj B.; Balci, Tugce B.; Callewaert, Bert; Calvo, Pier Luigi; Carli, Diana; Caudle, Michelle; Colaiacovo, Samantha; Cross, Laura; Demetriou, Kalliope; Drazba, Katy; Dutra‐Clarke, Marina; Edwards, Matthew; Genetti, Casie A.; Grange, Dorothy K.; Hickey, Scott E.; Isidor, Bertrand; Küry, Sébastien; Lachman, Herbert M.; Lavillaureix, Alinoë; Lyons, Michael J.; Marcelis, Carlo; Marco, Elysa J.; Martinez‐Agosto, Julian A.; Nowak, C.; Pizzol, Antonio; Planes, Marc; Prijoles, Eloise J.; Riberi, Evelise; Rush, Eric T.; Russell, Bianca; Sachdev, Rani; Schmalz, Betsy; Shears, Deborah; Stevenson, David A.; Wilson, Kate; Jansen, Sandra; Vries, Bert B.A. de; Curry, Cynthia J.

doi:10.1002/ajmg.a.63226

Cited by 5 publications

(4 citation statements)

References 25 publications

(41 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These mutations result in functionally active, truncated mutant proteins like those exhibited in human cancers and CH. Lymphoblastoid cell lines (LCLs) were generated from these JdVS patients by Jansen et al, 2017 ; Wojcik et al, 2023 .…”

Section: Resultsmentioning

confidence: 99%

SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells

Zhang,

Hsu,

Braekeleer

et al. 2024

eLife

Self Cite

View full text Add to dashboard Cite

The DNA damage response is critical for maintaining genome integrity and is commonly disrupted in the development of cancer. PPM1D (protein phosphatase, Mg2+/Mn2+ dependent 1D) is a master negative regulator of the response; gain-of-function mutations and amplifications of PPM1D are found across several human cancers making it a relevant pharmacologic target. Here, we used CRISPR/Cas9 screening to identify synthetic-lethal dependencies of PPM1D, uncovering superoxide dismutase-1 (SOD1) as a potential target for PPM1D-mutant cells. We revealed a dysregulated redox landscape characterized by elevated levels of reactive oxygen species and a compromised response to oxidative stress in PPM1D-mutant cells. Moreover, we observed marked genomic instability in mutant cells, which is exacerbated upon inhibition of SOD1. Altogether, our results demonstrate the protective role of SOD1 against oxidative stress and DNA damage in PPM1D-mutant leukemia cells and highlight a new potential therapeutic strategy against PPM1D-mutant cancers.

show abstract

Section: Resultsmentioning

confidence: 99%

SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells

Zhang,

Hsu,

Braekeleer

et al. 2024

eLife

Self Cite

View full text Add to dashboard Cite

show abstract

“…Finally, it is important to consider the microglia findings in the context of the increased infections that occur in some JdVS children. In the original report of 14 cases, and a subsequent follow up of 33 cases, recurrent infections, in particular otitis media, were reported in approximately half (1,4). Although this has not been evaluated systematically, the increase in infections seen in some children has been sufficiently severe to warrant evaluations for immunodeficiencies by their physicians, which have been non-diagnostic so far.…”

Section: Discussionmentioning

confidence: 99%

“…Jansen de Vries Syndrome (JdVS) (OMIM 617450) is a recently discovered neurodevelopmental disorder (NDD) caused by truncating mutations in PPM1D exons 5 or 6 (1)(2)(3)(4). It is characterized by mild to severe intellectual disability, anxiety disorder, attention deficit hyperactivity disorder (ADHD), obsessive behavior, hypotonia, sensory integration problems, and in some cases, autism spectrum disorder (ASD).…”

Section: Introductionmentioning

confidence: 99%

Proteomics and phosphoproteomics profiling in glutamatergic neurons and microglia in an iPSC model of Jansen de Vries Syndrome

Aguilan,

Pedrosa,

Dolstra

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

Background: Jansen de Vries Syndrome (JdVS) is a rare neurodevelopmental disorder (NDD) caused by gain-of-function (GOF) truncating mutations in PPM1D exons 5 or 6. PPM1D is a serine/threonine phosphatase that plays an important role in the DNA damage response (DDR) by negatively regulating TP53 (P53). JdVS-associated mutations lead to the formation of a truncated PPM1D protein that retains catalytic activity and has a GOF effect because of reduced degradation. Somatic PPM1D exons 5 and 6 truncating mutations are well-established factors in a number of cancers, due to excessive dephosphorylation and reduced function of P53 and other substrates involved in DDR. Children with JdVS have a variety of neurodevelopmental, psychiatric, and physical problems. In addition, a small fraction has acute neuropsychiatric decompensation apparently triggered by infection or severe non-infectious environmental stress factors. Methods: To understand the molecular basis of JdVS, we developed an induced pluripotent stem cell (iPSC) model system. iPSCs heterozygous for the truncating variant (PPM1D+/tr), were made from a patient, and control lines engineered using CRISPR-Cas9 gene editing. Proteomics and phosphoprotemics analyses were carried out on iPSC-derived glutamatergic neurons and microglia from three control and three PPM1D+/tr iPSC lines. We also analyzed the effect of the TLR4 agonist, lipopolysaccharide, to understand how activation of the innate immune system in microglia could account for acute behavioral decompensation. Results: One of the major findings was the downregulation of POGZ in unstimulated microglia. Since loss-of-function variants in the POGZ gene are well-known causes of autism spectrum disorder, the decrease in PPM1D+/tr microglia suggests this plays a role in the neurodevelopmental aspects of JdVS. In addition, neurons, baseline, and LPS-stimulated microglia show marked alterations in the expression of several E3 ubiquitin ligases, most notably UBR4, and regulators of innate immunity, chromatin structure, ErbB signaling, and splicing. In addition, pathway analysis points to overlap with neurodegenerative disorders. Limitations: Owing to the cost and labor-intensive nature of iPSC research, the sample size was small. Conclusions: Our findings provide insight into the molecular basis of JdVS and can be extrapolated to understand neuropsychiatric decompensation that occurs in subgroups of patients with ASD and other NDDs.

show abstract

“…25) had 2 molecular results (G6PD [OMIM 305900] and COL4A3 [OMIM 120070]) (Table 3). [51][52][53][54][55][56][57][58][59][60] Sequence analysis uncovered 33 of 47 of all at-risk genotypes (…”

Section: Positive Gs Findingsmentioning

confidence: 99%

At-Risk Genomic Findings for Pediatric-Onset Disorders From Genome Sequencing vs Medically Actionable Gene Panel in Proactive Screening of Newborns and Children

et al. 2023

View full text Add to dashboard Cite

ImportanceAlthough the clinical utility of genome sequencing for critically ill children is well recognized, its utility for proactive pediatric screening is not well explored.ObjectiveTo evaluate molecular findings from screening ostensibly healthy children with genome sequencing compared with a gene panel for medically actionable pediatric conditions.Design, Setting, and ParticipantsThis case series study was conducted among consecutive, apparently healthy children undergoing proactive genetic screening for pediatric disorders by genome sequencing (n = 562) or an exome-based panel of 268 genes (n = 606) from March 1, 2018, through July 31, 2022.ExposuresGenetic screening for pediatric-onset disorders using genome sequencing or an exome-based panel of 268 genes.Main Outcomes and MeasuresMolecular findings indicative of genetic disease risk.ResultsOf 562 apparently healthy children (286 girls [50.9%]; median age, 29 days [IQR, 9-117 days]) undergoing screening by genome sequencing, 46 (8.2%; 95% CI, 5.9%-10.5%) were found to be at risk for pediatric-onset disease, including 22 children (3.9%) at risk for high-penetrance disorders. Sequence analysis uncovered molecular diagnoses among 32 individuals (5.7%), while copy number variant analysis uncovered molecular diagnoses among 14 individuals (2.5%), including 4 individuals (0.7%) with chromosome scale abnormalities. Overall, there were 47 molecular diagnoses, with 1 individual receiving 2 diagnoses; of the 47 potential diagnoses, 22 (46.8%) were associated with high-penetrance conditions. Pathogenic variants in medically actionable pediatric genes were found in 6 individuals (1.1%), constituting 12.8% (6 of 47) of all diagnoses. At least 1 pharmacogenomic variant was reported for 89.0% (500 of 562) of the cohort. In contrast, of 606 children (293 girls [48.3%]; median age, 26 days [IQR, 10-67 days]) undergoing gene panel screening, only 13 (2.1%; 95% CI, 1.0%-3.3%) resulted in potential childhood-onset diagnoses, a significantly lower rate than those screened by genome sequencing (P &lt; .001).Conclusions and RelevanceIn this case series study, genome sequencing as a proactive screening approach for children, due to its unrestrictive gene content and technical advantages in comparison with an exome-based gene panel for medically actionable childhood conditions, uncovered a wide range of heterogeneous high-penetrance pediatric conditions that could guide early interventions and medical management.

show abstract

Jansen‐de Vries syndrome: Expansion of the PPM1D clinical and phenotypic spectrum in 34 families

Cited by 5 publications

References 25 publications

SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells

SOD1 is a synthetic-lethal target in PPM1D-mutant leukemia cells

Proteomics and phosphoproteomics profiling in glutamatergic neurons and microglia in an iPSC model of Jansen de Vries Syndrome

At-Risk Genomic Findings for Pediatric-Onset Disorders From Genome Sequencing vs Medically Actionable Gene Panel in Proactive Screening of Newborns and Children

Contact Info

Product

Resources

About