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

Teresa Santiago-Sim, Lindsay C Burrage, Frédéric Ebstein, Mari J Tokita, Marcus Miller, Weimin Bi, Alicia A Braxton, Jill A Rosenfeld, Maher Shahrour, Andrea Lehmann, Benjamin Cogné, Sébastien Küry, Thomas Besnard, Bertrand Isidor, Stéphane Bézieau, Isabelle Hazart, Honey Nagakura, LaDonna L Immken, Rebecca O Littlejohn, Elizabeth RoederBulent Kara, Katia Hardies, Sarah Weckhuysen, Patrick May, Johannes R Lemke, Orly Elpeleg, Bassam Abu-Libdeh, Kiely N James, Jennifer L Silhavy, Mahmoud Y Issa, Maha S Zaki, Joseph G Gleeson, John R Seavitt, Mary E Dickinson, M Cecilia Ljungberg, Sara Wells, Sara J Johnson, Lydia Teboul, Christine M Eng, Yaping Yang, Peter-Michael Kloetzel, Jason D Heaney, Magdalena A Walkiewicz, EuroEPINOMICS RES Consortium Autosomal Recessive working group, S. Hande Caglayan, Pasquale Striano, Federico Zara

Research output: Contribution to journalArticle

10 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)676-688
Number of pages13
JournalAmerican Journal of Human Genetics
Volume100
Issue number4
DOIs
Publication statusPublished - Apr 6 2017

Fingerprint

Ubiquitin
Intellectual Disability
Seizures
Ubiquitination
Microcephaly
Proteins
Muscle Hypotonia
Congenital Heart Defects
Chymotrypsin
Proteasome Endopeptidase Complex
Post Translational Protein Processing
Knockout Mice
Proteolysis
Heart Diseases
Blood Cells
Alleles
Brain
Growth
Neoplasms
Deubiquitinating Enzymes

Keywords

  • Abnormalities, Multiple
  • Adolescent
  • Animals
  • Child
  • Child, Preschool
  • Disease Models, Animal
  • Endopeptidases
  • Female
  • Gene Deletion
  • Humans
  • Intellectual Disability
  • Male
  • Mice
  • Pedigree
  • Proteasome Endopeptidase Complex
  • Seizures
  • Journal Article

Cite this

Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features. / Santiago-Sim, Teresa; Burrage, Lindsay C; Ebstein, Frédéric; Tokita, Mari J; Miller, Marcus; Bi, Weimin; Braxton, Alicia A; Rosenfeld, Jill A; Shahrour, Maher; Lehmann, Andrea; Cogné, Benjamin; Küry, Sébastien; Besnard, Thomas; Isidor, Bertrand; Bézieau, Stéphane; Hazart, Isabelle; Nagakura, Honey; Immken, LaDonna L; Littlejohn, Rebecca O; Roeder, Elizabeth; Kara, Bulent; Hardies, Katia; Weckhuysen, Sarah; May, Patrick; Lemke, Johannes R; Elpeleg, Orly; Abu-Libdeh, Bassam; James, Kiely N; Silhavy, Jennifer L; Issa, Mahmoud Y; Zaki, Maha S; Gleeson, Joseph G; Seavitt, John R; Dickinson, Mary E; Ljungberg, M Cecilia; Wells, Sara; Johnson, Sara J; Teboul, Lydia; Eng, Christine M; Yang, Yaping; Kloetzel, Peter-Michael; Heaney, Jason D; Walkiewicz, Magdalena A; EuroEPINOMICS RES Consortium Autosomal Recessive working group, S. Hande Caglayan ; Striano, Pasquale; Zara, Federico.

In: American Journal of Human Genetics, Vol. 100, No. 4, 06.04.2017, p. 676-688.

Research output: Contribution to journalArticle

Santiago-Sim, T, Burrage, LC, Ebstein, F, Tokita, MJ, Miller, M, Bi, W, Braxton, AA, Rosenfeld, JA, Shahrour, M, Lehmann, A, Cogné, B, Küry, S, Besnard, T, Isidor, B, Bézieau, S, Hazart, I, Nagakura, H, Immken, LL, Littlejohn, RO, Roeder, E, Kara, B, Hardies, K, Weckhuysen, S, May, P, Lemke, JR, Elpeleg, O, Abu-Libdeh, B, James, KN, Silhavy, JL, Issa, MY, Zaki, MS, Gleeson, JG, Seavitt, JR, Dickinson, ME, Ljungberg, MC, Wells, S, Johnson, SJ, Teboul, L, Eng, CM, Yang, Y, Kloetzel, P-M, Heaney, JD, Walkiewicz, MA, EuroEPINOMICS RES Consortium Autosomal Recessive working group, S. Hande Caglayan, Striano, P & Zara, F 2017, 'Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features', American Journal of Human Genetics, vol. 100, no. 4, pp. 676-688. https://doi.org/10.1016/j.ajhg.2017.03.001
Santiago-Sim, Teresa ; Burrage, Lindsay C ; Ebstein, Frédéric ; Tokita, Mari J ; Miller, Marcus ; Bi, Weimin ; Braxton, Alicia A ; Rosenfeld, Jill A ; Shahrour, Maher ; Lehmann, Andrea ; Cogné, Benjamin ; Küry, Sébastien ; Besnard, Thomas ; Isidor, Bertrand ; Bézieau, Stéphane ; Hazart, Isabelle ; Nagakura, Honey ; Immken, LaDonna L ; Littlejohn, Rebecca O ; Roeder, Elizabeth ; Kara, Bulent ; Hardies, Katia ; Weckhuysen, Sarah ; May, Patrick ; Lemke, Johannes R ; Elpeleg, Orly ; Abu-Libdeh, Bassam ; James, Kiely N ; Silhavy, Jennifer L ; Issa, Mahmoud Y ; Zaki, Maha S ; Gleeson, Joseph G ; Seavitt, John R ; Dickinson, Mary E ; Ljungberg, M Cecilia ; Wells, Sara ; Johnson, Sara J ; Teboul, Lydia ; Eng, Christine M ; Yang, Yaping ; Kloetzel, Peter-Michael ; Heaney, Jason D ; Walkiewicz, Magdalena A ; EuroEPINOMICS RES Consortium Autosomal Recessive working group, S. Hande Caglayan ; Striano, Pasquale ; Zara, Federico. / Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features. In: American Journal of Human Genetics. 2017 ; Vol. 100, No. 4. pp. 676-688.
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T1 - Biallelic Variants in OTUD6B Cause an Intellectual Disability Syndrome Associated with Seizures and Dysmorphic Features

AU - Santiago-Sim, Teresa

AU - Burrage, Lindsay C

AU - Ebstein, Frédéric

AU - Tokita, Mari J

AU - Miller, Marcus

AU - Bi, Weimin

AU - Braxton, Alicia A

AU - Rosenfeld, Jill A

AU - Shahrour, Maher

AU - Lehmann, Andrea

AU - Cogné, Benjamin

AU - Küry, Sébastien

AU - Besnard, Thomas

AU - Isidor, Bertrand

AU - Bézieau, Stéphane

AU - Hazart, Isabelle

AU - Nagakura, Honey

AU - Immken, LaDonna L

AU - Littlejohn, Rebecca O

AU - Roeder, Elizabeth

AU - Kara, Bulent

AU - Hardies, Katia

AU - Weckhuysen, Sarah

AU - May, Patrick

AU - Lemke, Johannes R

AU - Elpeleg, Orly

AU - Abu-Libdeh, Bassam

AU - James, Kiely N

AU - Silhavy, Jennifer L

AU - Issa, Mahmoud Y

AU - Zaki, Maha S

AU - Gleeson, Joseph G

AU - Seavitt, John R

AU - Dickinson, Mary E

AU - Ljungberg, M Cecilia

AU - Wells, Sara

AU - Johnson, Sara J

AU - Teboul, Lydia

AU - Eng, Christine M

AU - Yang, Yaping

AU - Kloetzel, Peter-Michael

AU - Heaney, Jason D

AU - Walkiewicz, Magdalena A

AU - EuroEPINOMICS RES Consortium Autosomal Recessive working group, S. Hande Caglayan

AU - Striano, Pasquale

AU - Zara, Federico

N1 - Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PY - 2017/4/6

Y1 - 2017/4/6

N2 - 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.

AB - 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.

KW - Abnormalities, Multiple

KW - Adolescent

KW - Animals

KW - Child

KW - Child, Preschool

KW - Disease Models, Animal

KW - Endopeptidases

KW - Female

KW - Gene Deletion

KW - Humans

KW - Intellectual Disability

KW - Male

KW - Mice

KW - Pedigree

KW - Proteasome Endopeptidase Complex

KW - Seizures

KW - Journal Article

U2 - 10.1016/j.ajhg.2017.03.001

DO - 10.1016/j.ajhg.2017.03.001

M3 - Article

C2 - 28343629

VL - 100

SP - 676

EP - 688

JO - American Journal of Human Genetics

JF - American Journal of Human Genetics

SN - 0002-9297

IS - 4

ER -