2. Academic Validation
  3. Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features

Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features

  • Am J Hum Genet. 2017 Apr 6;100(4):676-688. doi: 10.1016/j.ajhg.2017.03.001.
Teresa Santiago-Sim 1,  Lindsay C Burrage 2,  Frédéric Ebstein 3,  Mari J Tokita 1,  Marcus Miller 1,  Weimin Bi 1,  Alicia A Braxton 1,  Jill A Rosenfeld 4,  Maher Shahrour 5,  Andrea Lehmann 3,  Benjamin Cogné 6,  Sébastien Küry 6,  Thomas Besnard 6,  Bertrand Isidor 7,  Stéphane Bézieau 6,  Isabelle Hazart 8,  Honey Nagakura 9,  LaDonna L Immken 9,  Rebecca O Littlejohn 10,  Elizabeth Roeder 11,  EuroEPINOMICS RES Consortium Autosomal Recessive working group, S. Hande Caglayan 12,  Bulent Kara 13,  Katia Hardies 14,  Sarah Weckhuysen 15,  Patrick May 16,  Johannes R Lemke 17,  Orly Elpeleg 18,  Bassam Abu-Libdeh 5,  Kiely N James 19,  Jennifer L Silhavy 19,  Mahmoud Y Issa 20,  Maha S Zaki 20,  Joseph G Gleeson 19,  John R Seavitt 4,  Mary E Dickinson 21,  M Cecilia Ljungberg 22,  Sara Wells 23,  Sara J Johnson 23,  Lydia Teboul 23,  Christine M Eng 1,  Yaping Yang 1,  Peter-Michael Kloetzel 24,  Jason D Heaney 25,  Magdalena A Walkiewicz 26
Affiliations

Affiliations

  • 1 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.
  • 2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
  • 3 Charité-Universitätsmedizin Berlin, Institute of Biochemistry, Charité Platz 1/Virchowweg 6, 10117 Berlin, Germany.
  • 4 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5 Department of Pediatrics and Genetics, Makassed Hospital and Al-Quds University, Jerusalem 91220, Palestine.
  • 6 CHU de Nantes, Service de Génétique Médicale, Nantes Cedex 1 44093, France.
  • 7 CHU de Nantes, Service de Génétique Médicale, Nantes Cedex 1 44093, France; INSERM, UMR-S 957, 1 Rue Gaston Veil, Nantes 44035, France.
  • 8 CHU de Nantes, Service de Pédiatrie, Nantes Cedex 1 44093, France.
  • 9 Specially for Children, Austin, TX 78723, USA.
  • 10 Department of Pediatrics, Baylor College of Medicine, San Antonio, TX 78207, USA.
  • 11 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.
  • 12 Department of Molecular Biology and Genetics, Bogazici University, Istanbul 34342, Turkey.
  • 13 Department of Pediatrics, Kocaeli University Medical Faculty, Kocaeli 41380, Turkey.
  • 14 Neurogenetics Group, Center of Molecular Neurology, VIB, Antwerp 2610, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium.
  • 15 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.
  • 16 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette 4362, Luxembourg.
  • 17 Institute of Human Genetics, University of Leipzig Hospitals and Clinics, 04103 Leipzig, Germany.
  • 18 Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
  • 19 Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, Department of Neurosciences, University of California, San Diego, CA 92093, USA.
  • 20 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
  • 21 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.
  • 22 The Jan and Dan Duncan Neurological Research Institute, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 23 Medical Research Council Harwell (Mammalian Genetics Unit and Mary Lyon Centre), Harwell, Oxfordshire OX11 0RD, UK.
  • 24 Charité-Universitätsmedizin Berlin, Institute of Biochemistry, Charité Platz 1/Virchowweg 6, 10117 Berlin, Germany; Berlin Institute of Health, 10117 Berlin, Germany.
  • 25 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.
  • 26 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.
PMID: 28343629 DOI: 10.1016/j.ajhg.2017.03.001
Abstract

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.

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