TY - JOUR
T1 - Haploinsufficiency of the E3 ubiquitin-protein ligase gene TRIP12 causes intellectual disability with or without autism spectrum disorders, speech delay, and dysmorphic features
AU - Zhang, Jing
AU - Gambin, Tomasz
AU - Yuan, Bo
AU - Szafranski, Przemyslaw
AU - Rosenfeld, Jill A.
AU - Balwi, Mohammed Al
AU - Alswaid, Abdulrahman
AU - Al-Gazali, Lihadh
AU - Shamsi, Aisha M.Al
AU - Komara, Makanko
AU - Ali, Bassam R.
AU - Roeder, Elizabeth
AU - McAuley, Laura
AU - Roy, Daniel S.
AU - Manchester, David K.
AU - Magoulas, Pilar
AU - King, Lauren E.
AU - Hannig, Vickie
AU - Bonneau, Dominique
AU - Denommé-Pichon, Anne Sophie
AU - Charif, Majida
AU - Besnard, Thomas
AU - Bézieau, Stéphane
AU - Cogné, Benjamin
AU - Andrieux, Joris
AU - Zhu, Wenmiao
AU - He, Weimin
AU - Vetrini, Francesco
AU - Ward, Patricia A.
AU - Cheung, Sau Wai
AU - Bi, Weimin
AU - Eng, Christine M.
AU - Lupski, James R.
AU - Yang, Yaping
AU - Patel, Ankita
AU - Lalani, Seema R.
AU - Xia, Fan
AU - Stankiewicz, Paweł
N1 - Publisher Copyright:
© 2017, Springer-Verlag Berlin Heidelberg.
PY - 2017/4/1
Y1 - 2017/4/1
N2 - 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.
AB - 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.
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U2 - 10.1007/s00439-017-1763-1
DO - 10.1007/s00439-017-1763-1
M3 - Article
C2 - 28251352
AN - SCOPUS:85014091107
SN - 0340-6717
VL - 136
SP - 377
EP - 386
JO - Human Genetics
JF - Human Genetics
IS - 4
ER -