Dataset Information

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

ABSTRACT:

Background

The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.

Methods

We used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.

Results

Twelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.

Conclusions

Our data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.

SUBMITTER: Johnson BV

PROVIDER: S-EPMC6925349 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

Johnson Brett V BV Kumar Raman R Oishi Sabrina S Alexander Suzy S Kasherman Maria M Vega Michelle Sanchez MS Ivancevic Atma A Gardner Alison A Domingo Deepti D Corbett Mark M Parnell Euan E Yoon Sehyoun S Oh Tracey T Lines Matthew M Lefroy Henrietta H Kini Usha U Van Allen Margot M Grønborg Sabine S Mercier Sandra S Küry Sébastien S Bézieau Stéphane S Pasquier Laurent L Raynaud Martine M Afenjar Alexandra A Billette de Villemeur Thierry T Keren Boris B Désir Julie J Van Maldergem Lionel L Marangoni Martina M Dikow Nicola N Koolen David A DA VanHasselt Peter M PM Weiss Marjan M Zwijnenburg Petra P Sa Joaquim J Reis Claudia Falcao CF López-Otín Carlos C Santiago-Fernández Olaya O Fernández-Jaén Alberto A Rauch Anita A Steindl Katharina K Joset Pascal P Goldstein Amy A Madan-Khetarpal Suneeta S Infante Elena E Zackai Elaine E Mcdougall Carey C Narayanan Vinodh V Ramsey Keri K Mercimek-Andrews Saadet S Pena Loren L Shashi Vandana V Schoch Kelly K Sullivan Jennifer A JA Pinto E Vairo Filippo F Pichurin Pavel N PN Ewing Sarah A SA Barnett Sarah S SS Klee Eric W EW Perry M Scott MS Koenig Mary Kay MK Keegan Catherine E CE Schuette Jane L JL Asher Stephanie S Perilla-Young Yezmin Y Smith Laurie D LD Rosenfeld Jill A JA Bhoj Elizabeth E Kaplan Paige P Li Dong D Oegema Renske R van Binsbergen Ellen E van der Zwaag Bert B Smeland Marie Falkenberg MF Cutcutache Ioana I Page Matthew M Armstrong Martin M Lin Angela E AE Steeves Marcie A MA Hollander Nicolette den ND Hoffer Mariëtte J V MJV Reijnders Margot R F MRF Demirdas Serwet S Koboldt Daniel C DC Bartholomew Dennis D Mosher Theresa Mihalic TM Hickey Scott E SE Shieh Christine C Sanchez-Lara Pedro A PA Graham John M JM Tezcan Kamer K Schaefer G B GB Danylchuk Noelle R NR Asamoah Alexander A Jackson Kelly E KE Yachelevich Naomi N Au Margaret M Pérez-Jurado Luis A LA Kleefstra Tjitske T Penzes Peter P Wood Stephen A SA Burne Thomas T Pierson Tyler Mark TM Piper Michael M Gécz Jozef J Jolly Lachlan A LA

Biological psychiatry 20190629 2

<h4>Background</h4>The X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorde ...[more]

PMID: 31443933

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Project description:BackgroundAlzheimer's disease (AD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are debilitating neurodegenerative diseases for which there are currently no cures. Familial cases with known genetic causes make up less than 10% of these diseases, and little is known about the underlying mechanisms that contribute to sporadic disease. Accordingly, it is important to expand investigations into possible pathways that may contribute to disease pathophysiology. Glycerophosphodiester phosphodiesterase 2 (GDE2 or GDPD5) is a membrane-bound enzyme that acts at the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers distinct proteins to the membrane. GDE2 abnormally accumulates in intracellular compartments in the brain of patients with AD, ALS, and ALS/FTD, indicative of GDE2 dysfunction. Mice lacking GDE2 (Gde2KO) show neurodegenerative changes such as neuronal loss, reduced synaptic proteins and synapse loss, and increased Aβ deposition, raising the possibility that GDE2 disruption in disease might contribute to disease pathophysiology. However, the effect of GDE2 loss on behavioral function and learning/memory has not been characterized.ResultsHere, we show that GDE2 is expressed throughout the adult mouse brain in areas including the cortex, hippocampus, habenula, thalamus, and amygdala. Gde2KO and WT mice were tested in a set of behavioral tasks between 7 and 16 months of age. Compared to WT, Gde2KO mice display moderate hyperactivity that becomes more pronounced with age across a variety of behavioral tests assessing novelty-induced exploratory activity. Additionally, Gde2KO mice show reduced startle response, with females showing additional defects in prepulse inhibition. No changes in anxiety-associated behaviors were found, but Gde2KOs show reduced sociability. Notably, aged Gde2KO mice demonstrate impaired short/long-term spatial memory and cued fear memory/secondary contextual fear acquisition.ConclusionsTaken together, these observations suggest that loss of GDE2 leads to behavioral deficits, some of which are seen in neurodegenerative disease models, implying that loss of GDE2 may be an important contributor to phenotypes associated with neurodegeneration.

Dataset Information

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

Background

Methods

Results

Conclusions

Publications

Partial Loss of USP9X Function Leads to a Male Neurodevelopmental and Behavioral Disorder Converging on Transforming Growth Factor β Signaling.

Similar Datasets

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