USP9X mutation defines a neurodevelopmental syndrome

Loss-of-function mutations in USP9X, encoding a deubiquitylating enzyme, had previously been associated with a severe neurodevelopmental disorder in females. A new study identifies partial loss-of-function mutations in USP9X in males with a similar disorder and expands our understanding of its roles in regulating key neurodevelopmental signaling pathways and mouse behavior. A companion paper defines key substrates for its deubiquitylating activity and an important role in regulating dendritic spine density.

The first study, published in Biological Psychiatry, was supported in part by an Explorer Award to SFARI Investigator Michael Piper. The authors identified nine de novo and three maternally inherited mutations in USP9X in males with a neurodevelopmental syndrome and marshalled a range of evidence to suggest that they represent partial loss-of-function mutations that are responsible for the associated phenotypes. These phenotypes typically included developmental delay, autism, delayed or absent speech, motor difficulties and hypoplastic corpus callosum, among others. In line with previous data, they found several of the mutations to affect TGF beta, Wnt or mTOR signaling in fibroblast cell lines. Finally, the authors reported that mice lacking Usp9x in embryonic forebrain had severe deficits in hippocampal-dependent learning and memory.

Piper and colleagues contributed to a second study, led by the lab of Peter Penzes, which was published in Neuron. In this paper, the authors found a key role for Usp9x in mice in regulating levels of proteins harboring ankyrin-repeat domains (ANKRD), many of which are associated with autism risk. They showed that alterations in the levels of ANKRD proteins in mice led to persistent changes in dendritic spine density as well as hyperactivity. All told, data from the two papers highlight USP9X as a multifunctional protein associated with neurodevelopmental phenotypes in both sexes.

Image of graph
Mapping pathogenic variants in USP9X. A schematic showing the position of identified USP9X variants. Those indicated above the protein are common variants from the gnomAD database, with their population frequencies noted in black or gray. Those below the protein are rare variants identified in individuals with a neurodevelopmental disorder, with their proposed classification (likely pathogenic, unknown significance, likely benign) indicated by color. Image from Johnson B.V. et al. (2020).


Partial loss of USP9X function leads to a male neurodevelopmental and behavioral disorder converging on transforming growth factor beta signaling.

Johnson B.V., Kumar R., Oishi S., Alexander S., Kasherman M., Vega M.S., Ivancevic A., Gardner A., Domingo D., Corbett M., Parnell E., Yoon S., Oh T., Lines M., Lefroy H., Kini U., Van Allen M., Grønborg S., Mercier S., Küry S., Bézieau S., Pasquier L., Raynaud M., Afenjar A., Billette de Villemeur T., Keren B., Désir J., Van Maldergem L., Marangoni M., Dikow N., Koolen D.A., VanHasselt P.M., Weiss M., Zwijnenburg P., Sa J., Reis C.F., López-Otín C., Santiago-Fernández O., Fernández-Jaén A., Rauch A., Steindl K., Joset P., Goldstein A., Madan-Khetarpal S., Infante E., Zackai E., Mcdougall C., Narayanan V., Ramsey K., Mercimek-Andrews S., Pena L., Shashi V., Undiagnosed Diseases Network, Schoch K., Sullivan J.A., Pinto E Vario F., Pichurin P.N., Ewing S.A., Barnett S.S., Klee E.W., Perry M.S., Koenig M.K., Keegan C.E., Schuette J.L., Asher S., Perilla-Young Y., Smith L.D., Rosenfeld J.A., Bhoj E., Kaplan P., Li D., Oegema R., van Binsbergen E., van der Zwaag B., Smeland M.F., Cutcutache I., Page M., Armstrong M., Lin A.E., Steeves M.A., den Hollander N., Hoffer M.J.V., Reijnders M.R.F., Demirdas S., Koboldt D.C., Bartholomew D., Mosher T.M., Hickey S.E., Shieh C., Sanchez-Lara P.A., Graham J.M. Jr., Tezcan K., Schaefer G.B., Danylchuk N.R., Asamoah A., Jackson K.E., Yachelevich N., Au M., Pérez-Jurado L.A., Kleefstra T., Penzes P., Wood S.A., Burne T., Pierson T.M., Piper M., Gécz J., Jolly L.A.

Biol. Psychiatry 87, 100-112 (January 14, 2020) PubMed

Usp9X controls ankyrin-repeat domain protein homeostasis during dendritic spine development.

Yoon S., Parnell E., Kasherman M., Forrest M.P., Myczek K., Premarathne S., Sanchez Vega M.C., Piper M., Burne T.H.J., Jolly L.A., Wood S.A., Penzes P.

Neuron 105, 506-521 (February 4, 2020) PubMed

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