TY - JOUR
T1 - USP27X variants underlying X-linked intellectual disability disrupt protein function via distinct mechanisms
AU - Koch, Intisar
AU - Slovik, Maya
AU - Zhang, Yuling
AU - Liu, Bingyu
AU - Rennie, Martin
AU - Konz, Emily
AU - Cogne, Benjamin
AU - Daana, Muhannad
AU - Davids, Laura
AU - Diets, Illja J.
AU - Gold, Nina B.
AU - Holtz, Alexander M.
AU - Isidor, Bertrand
AU - Mor-Shaked, Hagar
AU - Neira Fresneda, Juanita
AU - Niederhoffer, Karen Y.
AU - Nizon, Mathilde
AU - Pfundt, Rolph
AU - Simon, Meh
AU - Stegmann, Apa
AU - Guillen Sacoto, Maria J
AU - Wevers, Marijke
AU - Barakat, Tahsin Stefan
AU - Yanovsky-Dagan, Shira
AU - Atanassov, Boyko S.
AU - Toth, Rachel
AU - Gao, Chengjiang
AU - Bustos, Francisco
AU - Harel, Tamar
N1 - © 2024 Koch et al.
PY - 2024/3
Y1 - 2024/3
N2 - Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.
AB - Neurodevelopmental disorders with intellectual disability (ND/ID) are a heterogeneous group of diseases driving lifelong deficits in cognition and behavior with no definitive cure. X-linked intellectual disability disorder 105 (XLID105, #300984; OMIM) is a ND/ID driven by hemizygous variants in the USP27X gene encoding a protein deubiquitylase with a role in cell proliferation and neural development. Currently, only four genetically diagnosed individuals from two unrelated families have been described with limited clinical data. Furthermore, the mechanisms underlying the disorder are unknown. Here, we report 10 new XLID105 individuals from nine families and determine the impact of gene variants on USP27X protein function. Using a combination of clinical genetics, bioinformatics, biochemical, and cell biology approaches, we determined that XLID105 variants alter USP27X protein biology via distinct mechanisms including changes in developmentally relevant protein-protein interactions and deubiquitylating activity. Our data better define the phenotypic spectrum of XLID105 and suggest that XLID105 is driven by USP27X functional disruption. Understanding the pathogenic mechanisms of XLID105 variants will provide molecular insight into USP27X biology and may create the potential for therapy development.
KW - Humans
KW - Intellectual Disability/genetics
KW - Cell Proliferation
KW - Computational Biology
KW - Neurogenesis
UR - http://www.scopus.com/inward/record.url?scp=85181849624&partnerID=8YFLogxK
U2 - 10.26508/lsa.202302258
DO - 10.26508/lsa.202302258
M3 - Article
C2 - 38182161
SN - 2575-1077
VL - 7
JO - Life Science Alliance
JF - Life Science Alliance
IS - 3
M1 - e202302258
ER -