KANSL1 haploinsufficiency causes Koolen-de Vries syndrome (KdVS), characterized by dysmorphic features and intellectual disability; amiable personality, congenital malformations and seizures also comm Show more
KANSL1 haploinsufficiency causes Koolen-de Vries syndrome (KdVS), characterized by dysmorphic features and intellectual disability; amiable personality, congenital malformations and seizures also commonly occur. The epilepsy phenotypic spectrum in KdVS is broad, but most individuals have focal seizures with some having a phenotype resembling the self-limited focal epilepsies of childhood (SFEC). We hypothesized that variants in KANSL1 contribute to pathogenesis of SFEC. We screened KANSL1 for single nucleotide variants in 90 patients with SFEC. We then screened a cohort of 208 patients with two specific SFEC syndromes, childhood epilepsy with centrotemporal spikes (CECTS) and atypical childhood epilepsy with centrotemporal spikes (ACECTS) for KANSL1 variants. The second cohort was also used to evaluate minor allelic variants that appeared overrepresented in the initial cohort. One variant, p.Lys104Thr, was predicted damaging and appeared overrepresented in our 90-patient cohort compared to Genome Aggregation Database (gnomAD) allele frequency (0.217 to 0.116, with no homozygotes in gnomAD). However, there was no difference in p.Lys104Thr allele frequency in the follow-up CECTS/ACECTS cohort and controls. Four rare KANSL1 variants of uncertain significance were identified in the CECTS/ACECTS cohort. Our data do not support a major role for KANSL1 variants in pathogenesis of SFEC. Show less
Alternative splicing (AS) is a widespread mechanism underlying the generation of proteomic and regulatory complexity. However, which of the myriad of human AS events play important roles in disease is Show more
Alternative splicing (AS) is a widespread mechanism underlying the generation of proteomic and regulatory complexity. However, which of the myriad of human AS events play important roles in disease is largely unknown. To identify frequently occurring AS events in lung cancer, we used AS microarray profiling and reverse transcription-PCR (RT-PCR) assays to survey patient-matched normal and adenocarcinoma tumor tissues from the lungs of 29 individuals diagnosed with non-small cell lung cancer (NSCLC). Of 5,183 profiled alternative exons, four displayed tumor-associated changes in the majority of the patients. These events affected transcripts from the VEGFA, MACF1, APP, and NUMB genes. Similar AS changes were detected in NUMB and APP transcripts in primary breast and colon tumors. Tumor-associated increases in NUMB exon 9 inclusion correlated with reduced levels of NUMB protein expression and activation of the Notch signaling pathway, an event that has been linked to tumorigenesis. Moreover, short hairpin RNA (shRNA) knockdown of NUMB followed by isoform-specific rescue revealed that expression of the exon 9-skipped (nontumor) isoform represses Notch target gene activation whereas expression of the exon 9-included (tumor) isoform lacks this activity and is capable of promoting cell proliferation. The results thus reveal widespread AS changes in NSCLC that impact cell signaling in a manner that likely contributes to tumorigenesis. Show less