Missense variant contribution to USP9X-female syndrome

Abstract

USP9X is an X-chromosome gene that escapes X-inactivation. Loss or compromised function of USP9X leads to neurodevelopmental disorders in males and females. While males are impacted primarily by hemizygous partial loss-of-function missense variants, in females de novo heterozygous complete loss-of-function mutations predominate, and give rise to the clinically recognisable USP9X-female syndrome. Here we provide evidence of the contribution of USP9X missense and small in-frame deletion variants in USP9X-female syndrome also. We scrutinise the pathogenicity of eleven such variants, ten of which were novel. Combined application of variant prediction algorithms, protein structure modelling, and assessment under clinically relevant guidelines universally support their pathogenicity. The core phenotype of this cohort overlapped with previous descriptions of USP9X-female syndrome, but exposed heightened variability. Aggregate phenotypic information of 35 currently known females with predicted pathogenic variation in USP9X reaffirms the clinically recognisable USP9X-female syndrome, and highlights major differences when compared to USP9X-male associated neurodevelopmental disorders.

Co-adaptor driven assembly of a CUL3 E3 ligase complex

“…Modification of PEF1 was visualized by western blotting for increasing amounts of reaction mix. ll mutation causes craniofacial malformation and autism as also observed upon CUL3 inactivation (Basar et al, 2021;De Rubeis et al, 2014;Jolly et al, 2020;Werner et al, 2015). In addition to the assembly inhibitor LNP, the formation of CUL3 KLHL12 complexes is therefore also controlled by reversible co-adaptor monoubiquitylation.…”

Compound genetic etiology in a patient with a syndrome including diabetes, intellectual deficiency and distichiasis

“…USP9X encodes an enzyme that plays a key role in human neural development and the p.Y1268C mutation has been shown to be involved in X-linked intellectual disability [ 9 ]. Furthermore, USP9X is an X-chromosome gene that escapes X-inactivation [ 25 ]. Female patients with de novo pathogenic mutations present with mild to moderate intellectual disability (motor and language delay), and several other clinical features (including notably urogenital abnormality, hearing impairment, cleft palate or bifid uvula) [ 26 ].…”

Acute Myeloid Leukemia-Related Proteins Modified by Ubiquitin and Ubiquitin-like Proteins

“…Located on the X-chromosome, USP9 is a member of the USP family [ 97 ]. Recent reports state that USP9X promotes or suppresses tumorigenesis in an environment-dependent manner [ 98 , 99 ].…”