Homozygous PLCB1 deletion associated with malignant migrating partial seizures in infancy

Abstract

Summary Malignant migrating partial seizures in infancy (MMPEI) is an early onset epileptic encephalopathy with few known etiologies. We sought to identify a novel cause of MMPEI in a child with MMPEI whose healthy parents were consanguineous. We used array comparative genomic hybridization (CGH) to identify copy number variants (CNVs) genome-wide and long-range PCR to further delineate the breakpoints of a deletion found by CGH. The proband had an inherited homozygous deletion of chromosome 20p13, disrupting the promoter region and first three coding exons of the gene PLCB1. Additional MMPEI cases were screened for similar deletions or mutations in PLCB1 but did not harbor mutations. Our results suggest that loss of PLCβ1 function is one cause of MMPEI, consistent with prior studies in a Plcb1 knockout mouse model that develops early onset epilepsy. We provide novel insight into the molecular mechanisms underlying MMPEI and further implicate PLCB1 as a candidate gene for severe childhood epilepsies. This work highlights the importance of pursuing genetic etiologies for severe early onset epilepsy syndromes.

Recent developments in the genetics of childhood epileptic encephalopathies: impact in clinical practice

“…Furthermore, CNVs appear to account for a few cases of EIMFS. Distinct studies revealed a 598 Kb microduplication at chromosome 16p11.2 25 , an 11.06 Mb deletion of chromosome 2q24.2q31.1, comprising more than 40 genes including SCN1A 20 and a deletion of chromosome 20p13, disrupting the phospholipase C, beta 1 gene PLCB1 26 . Even with these recent advances regarding the genetic basis of EIMFS, the etiology of a number cases remain unclear, as other studies investigating candidates genes failed to identify potential disease-causing mutations…”

Genomic profiling screens small molecules of metastatic prostate carcinoma

“…Among these genes, MBNL1, MBNL2 and CELF2 regulate the alternative splicing of genes (30)(31)(32), KPNA4 is a localization signal protein in the cytoplasm (33), and ZFP36L1 is an important transcription factor response to growth factors (34). SYT1 is a Ca 2+ signaling reception protein in the cytoplasmic membrane (35), PLCB1 catalyzes phosphatidylinositol-4,5-bisphosphate to inositol-1,4,5-trisphosphate and diacylglycerol (36), and SPRED1 regulates intracellular signaling pathway mitogen-activated protein kinase activation (37). RNF165 and MEF2C regulate cell movement (38).…”

The Genetics of the Epilepsies

“…Mutations in potassium channel genes KCNQ2 and KCNQ3 also result in a variety of epilepsy phenotypes [18,19]. Other mechanisms include DNA transcription regulation (e.g., ARX) [20], cell-cell adhesion and synaptic connection (e.g., PCDH19) [21], modulation of synaptic vesicle docking and release (e.g., STXBP1 and SPTAN1) [22], synaptic vesicle endocytosis (e.g., DNM1) [23], cell signaling (e.g., CDKL5 and PLCB1) [24,25], DNA repair (e.g., PNKP) [26], and enzyme function in metabolic pathways (e.g., PNPO) [27,28].…”

“…While KCNT1 mutations account for about one third of reported cases of EIMFS, the other genetically defined cases are caused by mutations in a number of other genes (SCN1A, SLC25A22, PLCB1, TBC1D24, SCN2A, QARS, SCN8A) [25,[55][56][57][58][59][60][61].…”