Unknown

Dataset Information

0

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


ABSTRACT: Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing (WES), we have identified, respectively, five deletion CNVs and four inactivating SNVs (two frameshifts, one missense, and one splicing) in TRIP12. Seven of these variants were found to be de novo; parental studies could not be completed in two families. Quantitative PCR analyses of the splicing mutation showed a dramatically decreased level of TRIP12 mRNA in the proband compared to the family controls, indicating a loss-of-function mechanism. The shared clinical features include intellectual disability with or without autistic spectrum disorders, speech delay, and facial dysmorphism. Our findings demonstrate that E3 ubiquitin ligase TRIP12 plays an important role in nervous system development and function. The nine presented pathogenic variants further document that TRIP12 haploinsufficiency causes a childhood-onset neurodevelopmental disorder. Finally, our data enable expansion of the phenotypic spectrum of ubiquitin-proteasome dependent disorders.

SUBMITTER: Zhang J 

PROVIDER: S-EPMC5543723 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

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 J   Gambin Tomasz T   Yuan Bo B   Szafranski Przemyslaw P   Rosenfeld Jill A JA   Balwi Mohammed Al MA   Alswaid Abdulrahman A   Al-Gazali Lihadh L   Shamsi Aisha M Al AMA   Komara Makanko M   Ali Bassam R BR   Roeder Elizabeth E   McAuley Laura L   Roy Daniel S DS   Manchester David K DK   Magoulas Pilar P   King Lauren E LE   Hannig Vickie V   Bonneau Dominique D   Denommé-Pichon Anne-Sophie AS   Charif Majida M   Besnard Thomas T   Bézieau Stéphane S   Cogné Benjamin B   Andrieux Joris J   Zhu Wenmiao W   He Weimin W   Vetrini Francesco F   Ward Patricia A PA   Cheung Sau Wai SW   Bi Weimin W   Eng Christine M CM   Lupski James R JR   Yang Yaping Y   Patel Ankita A   Lalani Seema R SR   Xia Fan F   Stankiewicz Paweł P  

Human genetics 20170301 4


Impairment of ubiquitin-proteasome system activity involving ubiquitin ligase genes UBE3A, UBE3B, and HUWE1 and deubiquitinating enzyme genes USP7 and USP9X has been reported in patients with neurodevelopmental delays. To date, only a handful of single-nucleotide variants (SNVs) and copy-number variants (CNVs) involving TRIP12, encoding a member of the HECT domain E3 ubiquitin ligases family on chromosome 2q36.3 have been reported. Using chromosomal microarray analysis and whole-exome sequencing  ...[more]

Similar Datasets

| S-EPMC7318102 | biostudies-literature
| S-EPMC7697007 | biostudies-literature
| S-EPMC7349372 | biostudies-literature
| S-EPMC3196520 | biostudies-literature
2018-10-13 | GSE121177 | GEO
| S-EPMC6972862 | biostudies-literature
| S-EPMC6397573 | biostudies-literature
| S-EPMC4022362 | biostudies-literature
| S-EPMC7948412 | biostudies-literature
| S-EPMC5630163 | biostudies-literature