Whole exome sequencing in Dandy-Walker variant with intellectual disability reveals an activating CIP2A mutation as novel genetic cause

Neurogenetics
Chin-An YangJan-Gowth Chang

Abstract

Dandy-Walker malformation (DWM) has been reported to have heterogeneous causes, including mutations in genes of fibroblast growth factors and in genes in the sonic hedgehog (Shh) signaling pathway. Here, we identified an activating cancerous inhibitor of protein phosphatase 2A (CIP2A) p.D269V mutation, located at the predicted protein-protein interaction groove, as a novel genetic cause of Dandy-Walker variant (DWV). CIP2A has been reported as an oncoprotein promoting tumor survival via inhibition of protein phosphatase 2A (PP2A). However, the impact of human germline CIP2A mutation is unknown. We report a novel heterozygous CIP2A p.D269V mutation via whole exome sequencing in two siblings with DWV and severe intellectual disability who were born to non-consanguineous parents. Only the older brother developed a slow-growing sacral leiomyoma in his teens. The CIP2A p.D269V mutation is associated with increased PP2A, mTOR, and c-Myc protein levels in peripheral blood mononuclear cells (PBMCs). The PP2A phosphatase activity, however, was not suppressed. Deep sequencing revealed that the father carries 16% of somatic CIP2A p.D269V mutation, suggesting potential inheritance from the mosaic sperm populations. Our study is the first t...Continue Reading

References

May 20, 2009·Bioinformatics·Heng Li, Richard Durbin
Jul 6, 2010·Nucleic Acids Research·Kai WangHakon Hakonarson
Aug 15, 2012·Immunological Reviews·Adam T Waickman, Jonathan D Powell
Jun 22, 2013·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Robert C GreenUNKNOWN American College of Medical Genetics and Genomics
Jun 26, 2013·Current Neurology and Neuroscience Reports·David A DymentKym M Boycott
Sep 13, 2013·Frontiers in Neuroanatomy·M Albert Basson, Richard J Wingate
Apr 24, 2016·Clinica Chimica Acta; International Journal of Clinical Chemistry·Nan GaiLing-Qian Wu
Dec 8, 2016·Cell Reports·Laura Kerosuo, Marianne E Bronner

❮ Previous
Next ❯

Citations

Oct 1, 2019·Chinese Medical Journal·Lei-Ming WangDe-Hong Lu
May 16, 2020·The Cerebellum·Christina T RüschEugen Boltshauser
Feb 4, 2021·The Cerebellum·Andrea AccogliMyriam Srour
Jul 10, 2021·Biochemical Society Transactions·Iris VerbinnenVeerle Janssens

❮ Previous
Next ❯

Methods Mentioned

BETA
exome sequencing
ELISA
immunoprecipitation
PCR

Software Mentioned

SIFT
VarScan
Bcl2fastq Conversion
BWA
ClinVar
CADD
ANNOVAR
GATK
NextSeq
PolyPhen

Related Concepts

Related Feeds

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.