Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features

Zhang, Jing; Gambin, Tomasz; Yuan, Bo; Szafrański, Przemysław; Rosenfeld, Jill A.; Balwi, Mohammed Al; Alswaid, Abdulrahman; Al‐Gazali, Lihadh; Shamsi, Aisha M. Al; Komara, Makanko; Ali, Bassam R.; Roeder, Elizabeth; McAuley, Laura; Roy, Daniel; Manchester, David K.; Magoulas, Pilar L.; King, Lauren E.; Hannig, Vickie; Bonneau, Dominique; Denommé‐Pichon, Anne‐Sophie; Charif, Majida; Besnard, Thomas; Bézieau, Stéphane; Cogné, Benjamin; Andrieux, Joris; Zhu, Wenmiao; He, Weimin; Vetrini, Francesco; Ward, Patricia A.; Cheung, Sau Wai; Bi, Weimin; Eng, Christine M.; Lupski, James R.; Yang, Yaping; Patel, Ankita; Lalani, Seema R.; Xia, Fan

doi:10.1007/s00439-017-1763-1

Cited by 38 publications

(35 citation statements)

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“…To further narrow the list of candidate disease-causing genes, we considered the following factors: (1) the number of de novo CNVs determined for each gene (Additional files 1 and 2 ); (2) additional CNVs < 5 Mb in size found in our cohort; (3) LOF variants found in ~ 15,000 WES cases (from BG and BHCMG “disease cohorts”); (4) phenotypic overlap among patients; (5) literature records supporting disease association; (6) predictions of haploinsufficiency [ 51 ] and intolerance to LOF [ 50 ] of the identified variants. Using these criteria, we found evidence supporting the contention of recently published disease genes, including BPTF (OMIM* 601819) [ 59 ], NONO (OMIM* 300084) [ 60 ], PSMD12 (OMIM* 604450) [ 61 ], TANGO2 (OMIM* 616830) [ 62 , 63 ], TRIP12 (OMIM* 604506) [ 64 , 65 ], and likely MAGED1 (OMIM* 300224) [ 66 ]. Furthermore, we found genes recently reported as disease-associated, including TBR1 (OMIM* 604616) [ 67 ] and CLTCL1 (OMIM* 601273) [ 68 ], as well as genes not yet associated with diseases.…”

Section: Resultssupporting

confidence: 76%

Identification of novel candidate disease genes from de novo exonic copy number variants

Gambin¹,

Yuan²,

Bi³

et al. 2017

Genome Med

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BackgroundExon-targeted microarrays can detect small (<1000 bp) intragenic copy number variants (CNVs), including those that affect only a single exon. This genome-wide high-sensitivity approach increases the molecular diagnosis for conditions with known disease-associated genes, enables better genotype–phenotype correlations, and facilitates variant allele detection allowing novel disease gene discovery.MethodsWe retrospectively analyzed data from 63,127 patients referred for clinical chromosomal microarray analysis (CMA) at Baylor Genetics laboratories, including 46,755 individuals tested using exon-targeted arrays, from 2007 to 2017. Small CNVs harboring a single gene or two to five non-disease-associated genes were identified; the genes involved were evaluated for a potential disease association.ResultsIn this clinical population, among rare CNVs involving any single gene reported in 7200 patients (11%), we identified 145 de novo autosomal CNVs (117 losses and 28 intragenic gains), 257 X-linked deletion CNVs in males, and 1049 inherited autosomal CNVs (878 losses and 171 intragenic gains); 111 known disease genes were potentially disrupted by de novo autosomal or X-linked (in males) single-gene CNVs. Ninety-one genes, either recently proposed as candidate disease genes or not yet associated with diseases, were disrupted by 147 single-gene CNVs, including 37 de novo deletions and ten de novo intragenic duplications on autosomes and 100 X-linked CNVs in males. Clinical features in individuals with de novo or X-linked CNVs encompassing at most five genes (224 bp to 1.6 Mb in size) were compared to those in individuals with larger-sized deletions (up to 5 Mb in size) in the internal CMA database or loss-of-function single nucleotide variants (SNVs) detected by clinical or research whole-exome sequencing (WES). This enabled the identification of recently published genes (BPTF, NONO, PSMD12, TANGO2, and TRIP12), novel candidate disease genes (ARGLU1 and STK3), and further confirmation of disease association for two recently proposed disease genes (MEIS2 and PTCHD1). Notably, exon-targeted CMA detected several pathogenic single-exon CNVs missed by clinical WES analyses.ConclusionsTogether, these data document the efficacy of exon-targeted CMA for detection of genic and exonic CNVs, complementing and extending WES in clinical diagnostics, and the potential for discovery of novel disease genes by genome-wide assay.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0472-7) contains supplementary material, which is available to authorized users.

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Section: Resultssupporting

confidence: 76%

Identification of novel candidate disease genes from de novo exonic copy number variants

Gambin¹,

Yuan²,

Bi³

et al. 2017

Genome Med

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“…Its dysregulation leads to various movement disturbances, dementia and hypogonadotropic hypogonadism [44,45]. Thus, it is not surprising that a growing group of ID proteins are directly involved in UPS-mediated protein degradation, such as UBE3A [46] [47], UBE2A [48,49,50,51], UBE3B [52,47], HUWE1 [53,54,55], MID1 [56][57][58][59], CUL4B [60,[61][62][63], UBR1 [64,65,66], TRIP12 [67][68][69], and RNF216 [45,[70][71][72].…”

Section: Discussionmentioning

confidence: 99%

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

et al. 2018

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RLIM, also known as RNF12, is an X-linked E3 ubiquitin ligase acting as a negative regulator of LIM-domain containing transcription factors and participates in X-chromosome inactivation (XCI) in mice. We report the genetic and clinical findings of 84 individuals from nine unrelated families, eight of whom who have pathogenic variants in RLIM (RING finger LIM domain-interacting protein). A total of 40 affected males have X-linked intellectual disability (XLID) and variable behavioral anomalies with or without congenital malformations. In contrast, 44 heterozygous female carriers have normal cognition and behavior, but eight showed mild physical features. All RLIM variants identified are missense changes cosegregating with the phenotype and predicted to affect protein function. Eight of the nine altered amino acids are conserved and lie either within a domain essential for binding interacting proteins or in the C-terminal RING finger catalytic domain. In vitro experiments revealed that these amino acid changes in the RLIM RING finger impaired RLIM ubiquitin ligase activity. In vivo experiments in rlim mutant zebrafish showed that wild type RLIM rescued the zebrafish rlim phenotype, whereas the patient-specific missense RLIM variants failed to rescue the phenotype and thus represent likely severe loss-of-function mutations. In summary, we identified a spectrum of RLIM missense variants causing syndromic XLID and affecting the ubiquitin ligase activity of RLIM, suggesting that enzymatic activity of RLIM is required for normal development, cognition and behavior.

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“…TRIP12 is a HECT-type E3 ubiquitin ligase that limits spreading of ubiquitylation marks surrounding DSBs by suppressing the accumulation of RNF168 in a UBR5 dependent manner 40 . Interestingly, haploinsufficiency of TRIP12 has been reported to cause intellectual disability 41 .…”

Section: Nuclear Interactome Of Endogenous Dyrk1amentioning

confidence: 99%

The nuclear interactome of DYRK1A reveals a functional role in DNA damage repair

Guard

Poss

Ebmeier

et al. 2018

Preprint

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Loss of function mutations in the protein kinase DYRK1A lead to a syndromic form of autism spectrum disorder and intellectual disability. Conversely, increased DYRK1A dosage is implicated in atypical brain development and neurocognitive deficits in trisomy 21. DYRK1A regulates a diverse array of cellular processes through kinase dependent and independent interactions with substrates and binding partners. Recent evidence implicates DYRK1A in direct regulation of the transcriptional machinery, but many of the molecular details are not yet known.Furthermore, the landscape of DYRK1A interactions in the nucleus is incomplete, impeding progress toward understanding its function in transcription. Here, we used immunoaffinity purification and mass spectrometry to identify nuclear interaction partners of endogenous DYRK1A. These were enriched in DNA damage repair factors, transcriptional elongation factors and E3 ubiquitin ligases. We validated an interaction with RNF169, a factor that promotes homology directed repair upon DNA damage. We further show that knockout of DYRK1A or treatment with DYRK1A inhibitors in HeLa cells impaired efficient recruitment of 53BP1 to DNA double strand breaks induced by ionizing radiation. This nuclear interactome thus reveals a new role for DYRK1A in DNA damage repair and provides a resource for exploring new functions of DYRK1A in the nucleus. MAIN BODY

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Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features

Cited by 38 publications

References 22 publications

Identification of novel candidate disease genes from de novo exonic copy number variants

Identification of novel candidate disease genes from de novo exonic copy number variants

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

The nuclear interactome of DYRK1A reveals a functional role in DNA damage repair

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