De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment Gene<i>CHAMP1</i>Cause Syndromic Intellectual Disability

Isidor, Bertrand; Küry, Sébastien; Rosenfeld, Jill A.; Besnard, Thomas; Schmitt, Sébastien; Joss, Shelagh; Davies, Sally; Lebel, Robert Roger; Henderson, Alex; Schaaf, Christian P.; Streff, Haley; Yang, Yaping; Jain, Vani; Chida, Nodoka; Latypova, Xénia; Caignec, Cédric Le; Cogné, Benjamin; Mercier, Sandra; Vincent, Marie‐Françoise; Colin, Estelle; Bonneau, Dominique; Denommé, Anne Sophie; Parent, Philippe; Gilbert‐Dussardier, Brigitte; Odent, Sylvie; Toutain, Annick; Piton, Amélie; Dina, Christian; Donnart, Audrey; Livet, Pierre; Charpentier, Eric; Redon, Richard; Iemura, Kenji; Ikeda, Masanori; Tanaka, Kozo; Bézieau, Stéphane

doi:10.1002/humu.22952

Cited by 42 publications

(65 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[22][23][24] These three variants were confirmed by Sanger sequencing. They were unique events observed in our inhouse database of about 350 exomes (including 75 trios from families with simplex ID) for subject 1 (HUGODIMS and CHU de Nantes); in over 40,000 exomes, including 2,300 trios with various developmental disorders, for subject 2 (Boston Children's Hospital and GeneDX); and in 2,500 trios with autism spectrum disorders for subject 3 (Simons Simplex Collection) ( Figure S2 (Figure 1 and Table S4).…”

Section: Congenital Malformationsmentioning

confidence: 74%

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Küry¹,

Besnard²,

Ebstein³

et al. 2017

The American Journal of Human Genetics

Self Cite

View full text Add to dashboard Cite

Degradation of proteins by the ubiquitin-proteasome system (UPS) is an essential biological process in the development of eukaryotic organisms. Dysregulation of this mechanism leads to numerous human neurodegenerative or neurodevelopmental disorders. Through a multi-center collaboration, we identified six de novo genomic deletions and four de novo point mutations involving PSMD12, encoding the non-ATPase subunit PSMD12 (aka RPN5) of the 19S regulator of 26S proteasome complex, in unrelated individuals with intellectual disability, congenital malformations, ophthalmologic anomalies, feeding difficulties, deafness, and subtle dysmorphic facial features. We observed reduced PSMD12 levels and an accumulation of ubiquitinated proteins without any impairment of proteasome catalytic activity. Our PSMD12 loss-of-function zebrafish CRISPR/Cas9 model exhibited microcephaly, decreased convolution of the renal tubules, and abnormal craniofacial morphology. Our data support the biological importance of PSMD12 as a scaffolding subunit in proteasome function during development and neurogenesis in particular; they enable the definition of a neurodevelopmental disorder due to PSMD12 variants, expanding the phenotypic spectrum of UPS-dependent disorders.Proteolysis by the ubiquitin-proteasome system (UPS) is a tightly regulated biological process in eukaryotic cells and is crucial for their homeostasis, signaling, and fate determination. 1-3 Proteins subjected to degradation are typically marked by polyubiquitin chains to be hydrolyzed in a precise, rapid, timely, and ATP-dependent manner by the 19S regulatory subunit of the 26S proteasome. 3-6 UPS-dependent degradation essentially contributes to proteostasis and plays a key role in neuronal development and function 7,8 by regulating synaptic plasticity, 9,10

show abstract

Section: Congenital Malformationsmentioning

confidence: 74%

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Küry¹,

Besnard²,

Ebstein³

et al. 2017

The American Journal of Human Genetics

Self Cite

View full text Add to dashboard Cite

show abstract

“…In addition to the above family, eight unrelated affected individuals with variants in EBF3 were identified through WES 10–14 by groups that independently submitted to GeneMatcher. In addition to c.625C>T (p.Arg209Trp), we found missense variants c.196A>G (p.Asn66Asp) in subject 4, c.422A>G (p.Tyr141Cys) in subject 7, c.512G>A (p.Gly171Asp) in subject 8, and c.530C>T (p.Pro177Leu) in subject 6; 9-bp duplication c.469_477dup (p.His157_ Ile159dup) in subject 10; nonsense variants c.907C>T (p.Arg303*) in subject 9 and c.913C>T (p.Gln305*) in subject 3; and splice-site mutation c.1101 + 1G>T in subject 5 (Figures 1A and 1B and Table S3).…”

mentioning

confidence: 99%

Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism

Harms

Girisha

Hardigan

et al. 2017

The American Journal of Human Genetics

Self Cite

View full text Add to dashboard Cite

From a GeneMatcher-enabled international collaboration, we identified ten individuals affected by intellectual disability, speech delay, ataxia, and facial dysmorphism and carrying a deleterious EBF3 variant detected by whole-exome sequencing. One 9-bp duplication and one splice-site, five missense, and two nonsense variants in EBF3 were found; the mutations occurred de novo in eight individuals, and the missense variant c.625C>T (p.Arg209Trp) was inherited by two affected siblings from their healthy mother, who is mosaic. EBF3 belongs to the early B cell factor family (also known as Olf, COE, or O/E) and is a transcription factor involved in neuronal differentiation and maturation. Structural assessment predicted that the five amino acid substitutions have damaging effects on DNA binding of EBF3. Transient expression of EBF3 mutant proteins in HEK293T cells revealed mislocalization of all but one mutant in the cytoplasm, as well as nuclear localization. By transactivation assays, all EBF3 mutants showed significantly reduced or no ability to activate transcription of the reporter gene CDKN1A, and in situ subcellular fractionation experiments demonstrated that EBF3 mutant proteins were less tightly associated with chromatin. Finally, in RNA-seq and ChIP-seq experiments, EBF3 acted as a transcriptional regulator, and mutant EBF3 had reduced genome-wide DNA binding and gene-regulatory activity. Our findings demonstrate that variants disrupting EBF3-mediated transcriptional regulation cause intellectual disability and developmental delay and are present in ~0.1% of individuals with unexplained neurodevelopmental disorders.

show abstract

“…Furthermore, two independent studies reported further 11 patients with de novo mutations in CHAMP1 (Isidor et al. ) (Tanaka et al. ).…”

mentioning

confidence: 99%

“…) (Isidor et al. ) (Tanaka et al. ), the biological evidence for linking between the patient mutations in CHAMP1 and ID is insufficient.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Disturbed chromosome segregation and multipolar spindle formation in a patient with CHAMP 1 mutation

Okamoto

Tsuchiya

Kuki

et al. 2017

Mol Genet Genomic Med

View full text Add to dashboard Cite

BackgroundPatients with intellectual disability (ID) typically exhibit significant defects in both intelligence and adaptive behavior. Aberration of several genes involved in proper progression of mitosis has been reported to underlie ID. Here, we report a new patient with a novel mutation of CHAMP1.MethodsWhole exome sequencing (WES) analysis was performed. We isolated lymphoblast cells from the CHAMP1 patient and observed chromosome segregation.ResultsWe identified a de novo frameshift mutation in CHAMP1. We find that these cells exhibit an increase in centrosome number and resulting multipolar spindle formation. The phenotypes observed in the patient's lymphoblastoid cells were presumably because of cytokinesis failure. We also confirm the identical phenotypes in human culture cells depleted of CHAMP1.Conclusion CHAMP1 encodes a protein regulating kinetochore–microtubule attachment and chromosome segregation. These data strongly support that CHAMP1 mutations cause ID, and suggest that CHAMP1 is critical for progression of cytokinesis and maintenance of centrosome number.

show abstract

De Novo Truncating Mutations in the Kinetochore-Microtubules Attachment GeneCHAMP1Cause Syndromic Intellectual Disability

Cited by 42 publications

References 18 publications

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

De Novo Disruption of the Proteasome Regulatory Subunit PSMD12 Causes a Syndromic Neurodevelopmental Disorder

Mutations in EBF3 Disturb Transcriptional Profiles and Cause Intellectual Disability, Ataxia, and Facial Dysmorphism

Disturbed chromosome segregation and multipolar spindle formation in a patient with CHAMP 1 mutation

Contact Info

Product

Resources

About