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

Abstract

Patient now 19 years old has intellectual disability, developmental delay, absent speech, seizures, hypotonia, severe motor disability (non-ambulatory), short stature, relative macrocephaly. Patient uses gastric tube for feeding and has gastroesophageal reflux. Facial dysmorphisms include short palpebral fissures, large incisors, full eyebrows. Fingers are short and trident-shaped.Brain MRI revealed progressive cerebral and cerebellar volume loss, hypodensity in the left basal ganglia, unchanged and consistent with a lacune infarct (remote). There is a less conspicuous area of hypodensity on the contralateral side. There are hypodense white matter changes along the periventricular white matter and bilateral centrum semiovale.

USP9X deubiquitinase couples the pluripotency network and cell metabolism to regulate ESC differentiation potential

“…A functional annotation of USP9X target genes show a significant enrichment for genes involved in "extracellular space", "cell metabolism", "cell differentiation" and "neurogenesis" ( Supplementary Table 4B-F). This later term is in accordance with a role of Usp9X in neuron development and physiopathology in the adult mice and in humans [31,33,36,37,39,55].…”

“…It is thus often extrapolated from these mRNA expression studies that USP9X is important to define pluripotency [4,41]. Our work clearly demonstrates that depletion of USP9X by shRNA or [36,37,49,50,70]. Our data suggest an additional function in ESC, with a new layer of regulation involving the regulation of LEFTY2 abundance, a secreted ligand that may act through cell autonomous and non-autonomous functions to regulate ESC fate.…”

“…Deubiquitinase USP9X (also known as FAM or Fat Facets in Mammals) is indispensable for embryonic development [31,32]. It plays a critical role in tissue development and homeostasis as exemplified by its implication in developmental disorders and cancers [33][34][35][36][37][38][39]. USP9X is very highly expressed in several stem cell populations compared to their differentiated counterparts, as well as in induced pluripotent cells, thus indicating USP9X expression as a marker of stemness [4,40,41].…”

Investigating cortical features of Sotos syndrome using mice heterozygous for Nsd1

“…This showed no significant differences between control and Nsd1 +/− mice in the domains of locomotion and activity, energy expenditure, body mass composition, food and water consumption or respiratory exchange (data not shown). To assess spatial learning and memory in Nsd1 +/− mice we performed the active place avoidance test . In this test, mice are placed on a rotating platform, and, over a course of consecutive trials, must learn to avoid the position of a stationary shock zone using visual cues on the surrounding walls (Figure 5A, B).…”

Molecular mechanisms underlying malformations of cortical development

“…Therefore, rather than investigating individual genes and the multiple pathways they may regulate, it would be more feasible to find network hubs of genes that have common pathways in abnormal developmental mechanisms leading to intellectual disability. Recently, the gene, ubiquitin specific protease 9 X-linked (USP9X), has been suggested to be a hub for regulating various factors involved in intellectual disability (Johnson et al, 2020;Kasherman et al, 2020). USP9X, a deubiquitylating enzyme, has been shown to regulate NSC proliferation and neuronal maturation (Jolly et al, 2009;Oishi et al, 2016).…”