Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features.
Ubiquitination is a posttranslational modification that regulates many cellular processes including protein degradation, intracellular trafficking, cell signaling, and protein-protein interactions. Deubiquitinating enzymes (DUBs), which reverse the process of ubiquitination, are important regulators of the ubiquitin system. OTUD6B encodes a member of the ovarian tumor domain (OTU)-containing subfamily of deubiquitinating enzymes. Herein, we report biallelic pathogenic variants in OTUD6B in 12 individuals from 6 independent families with an intellectual disability syndrome associated with seizures and dysmorphic features. In subjects with predicted loss-of-function alleles, additional features include global developmental delay, microcephaly, absent speech, hypotonia, growth retardation with prenatal onset, feeding difficulties, structural brain abnormalities, congenital malformations including congenital heart disease, and musculoskeletal features. Homozygous Otud6b knockout mice were subviable, smaller in size, and had congenital heart defects, consistent with the severity of loss-of-function variants in humans. Analysis of peripheral blood mononuclear cells from an affected subject showed reduced incorporation of 19S subunits into 26S proteasomes, decreased chymotrypsin-like activity, and accumulation of ubiquitin-protein conjugates. Our findings suggest a role for OTUD6B in proteasome function, establish that defective OTUD6B function underlies a multisystemic human disorder, and provide additional evidence for the emerging relationship between the ubiquitin system and human disease.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX 77021, USA.
Teresa
T
Santiago-Sim
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
Lindsay C
LC
Burrage
Charité-Universitätsmedizin Berlin, Institute of Biochemistry, Charité Platz 1/Virchowweg 6, 10117 Berlin, Germany.
Frédéric
F
Ebstein
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX 77021, USA.
Mari J
MJ
Tokita
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX 77021, USA.
Marcus
M
Miller
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX 77021, USA.
Weimin
W
Bi
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX 77021, USA.
Alicia A
AA
Braxton
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Jill A
JA
Rosenfeld
Department of Pediatrics and Genetics, Makassed Hospital and Al-Quds University, Jerusalem 91220, Palestine.
Maher
M
Shahrour
Charité-Universitätsmedizin Berlin, Institute of Biochemistry, Charité Platz 1/Virchowweg 6, 10117 Berlin, Germany.
Andrea
A
Lehmann
CHU de Nantes, Service de Génétique Médicale, Nantes Cedex 1 44093, France.
Benjamin
B
Cogné
CHU de Nantes, Service de Génétique Médicale, Nantes Cedex 1 44093, France.
Sébastien
S
Küry
CHU de Nantes, Service de Génétique Médicale, Nantes Cedex 1 44093, France.
Thomas
T
Besnard
CHU de Nantes, Service de Génétique Médicale, Nantes Cedex 1 44093, France; INSERM, UMR-S 957, 1 Rue Gaston Veil, Nantes 44035, France.
Bertrand
B
Isidor
CHU de Nantes, Service de Génétique Médicale, Nantes Cedex 1 44093, France.
Stéphane
S
Bézieau
CHU de Nantes, Service de Pédiatrie, Nantes Cedex 1 44093, France.
Isabelle
I
Hazart
Specially for Children, Austin, TX 78723, USA.
Honey
H
Nagakura
Specially for Children, Austin, TX 78723, USA.
LaDonna L
LL
Immken
Department of Pediatrics, Baylor College of Medicine, San Antonio, TX 78207, USA.
Rebecca O
RO
Littlejohn
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, San Antonio, TX 78207, USA.
Elizabeth
E
Roeder
Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey.
Department of Pediatrics, Kocaeli University Medical Faculty, Kocaeli 41380, Turkey.
Bulent
B
Kara
Neurogenetics Group, Center of Molecular Neurology, VIB, Antwerp 2610, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium.
Katia
K
Hardies
Neurogenetics Group, Center of Molecular Neurology, VIB, Antwerp 2610, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium; Division of Neurology, Antwerp University Hospital, Antwerp 2610, Belgium.
Sarah
S
Weckhuysen
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette 4362, Luxembourg.
Patrick
P
May
Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 04103 Leipzig, Germany.
Johannes R
JR
Lemke
Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
Orly
O
Elpeleg
Department of Pediatrics and Genetics, Makassed Hospital and Al-Quds University, Jerusalem 91220, Palestine.
Bassam
B
Abu-Libdeh
Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, CA 92093, USA.
Kiely N
KN
James
Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, CA 92093, USA.
Jennifer L
JL
Silhavy
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Mahmoud Y
MY
Issa
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
Maha S
MS
Zaki
Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, CA 92093, USA.
Joseph G
JG
Gleeson
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
John R
JR
Seavitt
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX 77030, USA.
Mary E
ME
Dickinson
The Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
M Cecilia
MC
Ljungberg
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
Sara
S
Wells
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
Sara J
SJ
Johnson
Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
Lydia
L
Teboul
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX 77021, USA.
Christine M
CM
Eng
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX 77021, USA.
Yaping
Y
Yang
Charité-Universitätsmedizin Berlin, Institute of Biochemistry, Charité Platz 1/Virchowweg 6, 10117 Berlin, Germany; Berlin Institute of Health, 10117 Berlin, Germany.
Peter-Michael
PM
Kloetzel
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: heaney@bcm.edu.
Jason D
JD
Heaney
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Miraca Genetics Laboratories, Baylor College of Medicine, Houston, TX 77021, USA. Electronic address: mwalkiew@bcm.edu.
Magdalena A
MA
Walkiewicz
D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D010450:Endopeptidases / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D051379:Mice; D010375:Pedigree; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism; D012640:Seizures / Q000235:genetics
D010450:Endopeptidases; C559912:OTUD6B protein, human; D046988:Proteasome Endopeptidase Complex