Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

Steklov, Mikhail; Pandolfi, Silvia; Baietti, Maria Francesca; Batiuk, A; Carai, Paolo; Najm, Paul; Zhang, M; Jang, Hyunbum; Renzi, Fabrizio; Cai, Yanyan; Asbagh, Layka Abbasi; Pastor, Tibor J.; Troyer, Magdalena De; Šimíček, Michal; Radælli, Enrico; Brems, Hilde; Legius, Eric; Tavernier, Jan; Gevaert, Kris; Impens, Francis; Messiaen, Ludwine; Nussinov, Ruth; Heymans, Stéphane; Eyckerman, Sven; Sablina, Anna

doi:10.1126/science.aap7607

Cited by 162 publications

(215 citation statements)

References 41 publications

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“…These disorders all result from dysregulation of RAS‐MAPK signalling so have collectively been termed the “RASopathies”. LZTR1 has only recently been functionally linked to RAS‐MAPK signalling, which explains why its role in NS long went unrecognised. For instance, the gene was absent from a list of 789 RAS–ERK pathway genes prioritised by Chen et al such that the pathogenicity of p.R237Q/p.A249P identified in that study was only realised subsequently .…”

Section: Discussionmentioning

confidence: 99%

Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

et al. 2019

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Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1‐ associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly‐acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound‐heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss‐of‐function mutations in NEB , consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities ( P = 0.0005), supporting a causal role for LZTR1 . Second, targeted sequencing of eight unsolved NS‐like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.‐38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1‐4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.

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Section: Discussionmentioning

confidence: 99%

Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

et al. 2019

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“…Human LZTR1 has been shown to interact with Cul3 in the Cul3 ubiquitin-ligase complex [27]. Cul3 in Drosophila has been associated with sleep and interacts physically in this regulation with Insomniac, another BTB/POZ-domain protein (like Nowl) that functions as a substrate adaptor in the Cul3 complex [15,30].…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have found that LZTR1 may function in the Cul3 ubiquitin ligase complex to ubiquitinate Ras [27,28], which has previously been implicated in sleep regulation [54]. Nf1 is an important regulator of Ras signaling, and mutations in Nf1 and LZTR1 both give rise to types of neurofibromatosis [17,55].…”

Section: Discussionmentioning

confidence: 99%

“…Human LZTR1 was recently shown to function through the Cul3-based ubiquitin ligase complex, as a component of which it is suggested to mediate substrate specificity [27,28]. Interestingly, Cul3 has also been implicated as a causative gene in psychiatric disorders [29] and has been shown to play an important role in Drosophila sleep [14,15,30].…”

Section: Drosophilamentioning

confidence: 99%

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Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control

Maurer

Malita

Nagy

et al. 2019

Preprint

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AbstractThe human 22q11.2 chromosomal deletion is one of the strongest identified genetic risk factors for schizophrenia. Although the deletion spans a number of genes, the contribution of each of these to the 22q11.2 deletion syndrome (DS) is not known. To investigate the effect of individual genes within this interval on the pathophysiology associated with the deletion, we analyzed their role in sleep, a behavior affected in virtually all psychiatric disorders, including the 22q11.2 DS. We identified the gene LZTR1 (night owl, nowl) as a regulator of sleep in Drosophila. Neuronal loss of nowl causes short and fragmented sleep, especially during the night. In humans, LZTR1 has been associated with Ras-dependent neurological diseases also caused by Neurofibromin-1 (Nf1) deficiency. We show that Nf1 loss leads to a night-time sleep phenotype nearly identical to that of nowl loss, and that nowl negatively regulates Ras and interacts with Nf1 in sleep regulation. We also show that nowl is required for metabolic homeostasis, suggesting that LZTR1 may contribute to the genetic susceptibility to obesity associated with the 22q11.2 DS. Furthermore, knockdown of nowl or Nf1 in GABA-responsive sleep-promoting neurons elicits the sleep-fragmentation phenotype, and this defect can be rescued by increased GABAA receptor signaling, indicating that Nowl promotes sleep by decreasing the excitability of GABA-responsive wake-driving neurons. Our results suggest that nowl/LZTR1 may be a conserved regulator of GABA signaling and sleep that contributes to the 22q11.2 DS.

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“…Under normal physiological conditions, rates of protein synthesis, modification and degradation are tightly regulated and vary significantly between the cell type, tissue, and molecule in question. In contrast, disruption of normal proteome dynamics is thought to be a key component of the aging process, as well as being implicated in abnormal tissue development (Medina-Cano et al, 2018), and diseases (Steklov et al, 2018) such as inflammation (Yin et al, 2019), Alzheimer disease (Xia, 2019), skeleton dysplasia, cancer and fibrosis (Stegen et al, 2019) . However, our current understanding of how protein expression patterns are modified over time and how this varies between different body compartments is extremely limited.…”

Section: Introductionmentioning

confidence: 99%

Dynamics of murine brain protein synthesisin vivoidentify the hippocampus, cortex and cerebellum as highly active metabolic sites

Park

Wang

et al. 2019

Preprint

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Special note:Due to the large file size and excel file format is not accepted by Biorxiv submission system, all the Tables (except Table1) in this manuscript have submitted as supplementary. AbstractIdentification of proteins that are synthesized de novo in response to specific microenvironmental cues is critical to understanding the molecular mechanisms that underpin key physiological processes and pathologies. Here we report that a brief period of pulsed SILAC diet (Stable Isotope Labelling by Amino acids in Cell culture) enables determination of biological functions corresponding to actively translating proteins in the mouse brain. Our data demonstrate that the hippocampus, cortex and cerebellum are highly active sites of protein synthesis, rapidly expressing key mediators of nutrient sensing and lipid metabolism, as well as critical regulators of synaptic function, axon guidance, and circadian entrainment. Together, these findings confirm that protein metabolic activity varies significantly between brain regions in vivo and indicate that pSILAC-based approaches can identify specific anatomical sites and biological pathways likely to be suitable for drug targeting in neurodegenerative disorders.

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Mutations in LZTR1 drive human disease by dysregulating RAS ubiquitination

Cited by 162 publications

References 41 publications

Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

Delineation of dominant and recessive forms of LZTR1‐associated Noonan syndrome

Analysis of genes within the schizophrenia-linked 22q11.2 deletion identifies interaction of night owl/LZTR1 and NF1 in GABAergic sleep control

Dynamics of murine brain protein synthesisin vivoidentify the hippocampus, cortex and cerebellum as highly active metabolic sites

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