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

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 to describe a pathogenic CIP2A mutation in humans, which might disrupt neuronal development via enhancing mTOR and c-Myc protein expressions, shedding light in mechanisms of DWV pathogenesis.

A Dandy-Walker malformation associated with ganglioglioma

“…Mutations of the sonic hedgehog ( Shh ) signaling pathway genes, zinc finger protein 1 ( ZIC1 ) and ZIC4 , as well as fibroblast growth factor genes ( FGF ) 8 and FGF17 have been implicated in DWM. [5] In our present case, no other pathological molecular alterations, including BRAF V600E , were found by next generation sequencing.…”

Protein Phosphatase 2A (PP2A) mutations in brain function, development, and neurologic disease

“…SGS patients suffer from severe ID/DD, have distinctive craniofacial features (mid-face retraction, bi-temporal narrowing, frontal bossing, hypertelorism, short upturned nose, low-set abnormal ears), seizures, microcephaly (75%), CC agenesis, genitourinary and renal malformations, cardiac defects (50%), and an increased cancer risk [112][113][114]. One variant (p.D269V) has been reported in CIP2A, as a novel Dandy-Walker variant, giving rise to severe ID, speech and motoric delay and characteristic brain abnormalities (hypoplasia of the vermis, enlarged fourth ventricle, atrophy of the pons, mild atrophy of the midbrain and normal posterior fossa) [115]. Although the functional characterisation of this CIP2A variant was rather poor, a gain-of-function was suggested [115].…”

“…One variant (p.D269V) has been reported in CIP2A, as a novel Dandy-Walker variant, giving rise to severe ID, speech and motoric delay and characteristic brain abnormalities (hypoplasia of the vermis, enlarged fourth ventricle, atrophy of the pons, mild atrophy of the midbrain and normal posterior fossa) [115]. Although the functional characterisation of this CIP2A variant was rather poor, a gain-of-function was suggested [115]. Finally, two homozygous nonsense variants (p.R112* and p.R151*) in BOD1 were reported in two independent consanguineous families, causally linked to moderate ID, mild facial dysmorphism, hearing impairment and endocrine abnormalities [79,116].…”

G9a inactivation in progenitor cells with Isl1-Cre with reduced recombinase activity models aspects of Dandy-Walker complex

“…The co-occurrence of such variations led to the hypothesis that altered development and migration of neural crest cells contributes to Dandy-Walker ( Coban et al, 2010 ; Squires et al, 1998 ). Genes regulating neural crest development, including Zic family member 1 and 4 ( ZIC1 , ZIC4 ) ( Blank et al, 2011 ), fibroblast growth factor 8 and 17 ( FGF8 , FGF17 ) ( Zanni et al, 2011 ), laminin subunit gamma 1( LAMC1 ) ( Darbro et al, 2013 ), forkhead box C1 ( FOXC1 ) ( Aldinger et al, 2009 ), forkhead box L2 ( FOXL2 ) ( Lim et al, 2011 ) and cellular inhibitor of PP2A ( CIP2A ) ( Yang et al, 2018 ), are mutated in Dandy-Walker. However, the contribution of abnormal neural crest progenitor development to Dandy-Walker complex has not been tested.…”