Microdeletion of pseudogene chr14.232.a affects LRFN5 expression in cells of a patient with autism spectrum disorder

Abstract

We identified a 14q21.2 microdeletion in a 16-year-old boy with autism spectrum disorder (ASD), IQ in the lower part of normal range but high-functioning memory skills. The deletion affects a gene desert, and the non-deleted gene closest to the microdeletion boundaries is LRFN5, which encodes a protein involved in synaptic plasticity and implicated in neuropsychiatric disorders. LRFN5 expression was significantly decreased in the proband's skin fibroblasts. The deleted region includes the pseudogene chr14.232.a, which is transcribed into a long non-coding RNA (lncLRFN5-10), whose levels were also significantly reduced in the proband's fibroblasts compared to controls. Transfection of the patient's fibroblasts with a plasmid expressing chr14.232.a significantly increased LRFN5 expression, while siRNA targeting chr14.232.a-derived lncLRFN5-10 reduced LRFN5 levels. In summary, we report on an individual with ASD carrying a microdeletion encompassing the pseudogene chr14.232.a encoding for lncLRFN5-10, which was found to affect the expression levels of the nearby, non-deleted LRFN5. This case illustrates the potential role of long non-coding RNAs in regulating expression of neighbouring genes with a functional role in ASD pathogenesis.

Autism risk gene POGZ promotes chromatin accessibility and expression of clustered synaptic genes

“…Slitrk1 is a Tourette’s disorder candidate gene (Abelson et al 2005; O’Roak et al 2010) and Slitrk5 mouse mutants have OCD like phenotypes (Shmelkov et al 2010). Lrfn5 , encoding another leucine-rich repeat extracellular protein implicated in NDDs (Cappuccio et al 2019), was down-regulated in Pogz −/− as well.…”

Interpreting the impact of noncoding structural variation in neurodevelopmental disorders

“…iPSC-derived neurons of patients with PTCHD1-AS deletions showed decreased excitatory synaptic activity, although PTCHD1 expression does not appear to be affected. This in contrast to lncLRFN5-10, which does appear to regulate expression of its nearby gene LRFN5 and was also found to be affected by a microdeletion in an ASD patient 80 . Translocations and deletions disrupting LINC00299 have been identified in patients with DD and ID 81,82 .…”

Bioinformatics analyses of significant genes, related pathways and candidate prognostic biomarkers in Alzheimer’s disease

“…Previous investigation demonstrates that RGS4 [83], CXCL11 [84], EGR1 [85], CALB1 [86], BDNF (brain derived neurotrophic factor) [87], TERT (telomerase reverse transcriptase) [88], NEFL (neurofilament light) [89], SNAP25 [90], RPH3A [91], NRN1 [92], SYT1 [93], GRIN2B [94], AVP (arginine vasopressin) [95], VSNL1 [96], HTR2A [97], PAK3 [98], STXBP5L [99], HCRTR2 [100], SYP (synaptophysin) [101], SYT10 [102], PRKCE (protein kinase C epsilon) [103], NRG1 [104], KISS1 [105], NRXN3 [106], RAB3A [107], IGF1 [108], PLK2 [109], CBLN4 [110], CAP2 [111], SV2B [112], CAMK4 [113], INA (internexin neuronal intermediate filament protein alpha) [114], GAP43 [115], TTR (transthyretin) [116], CXCR2 [117], IL1R2 [118], CXCR4 [119], CCR2 [120], MYOCD (myocardin) [121], S100A12 [122], CXCR3 [123], PROK2 [124], CXCL8 [125], RGS1 [126], NOTCH3 [127], P2RX7 [128], NGFR (nerve growth factor receptor) [129], GDF15 [130], CR1 [131], ADORA2A [132], GPER1 [133], FCGR2B [134], MMP9 [135], CNN2 [136], C5AR1 [137], CCL15 [138], RBPMS (RNA binding protein, mRNA processing factor) [139], TBX2 [140], FPR2 [141], PCK1 [142], ADH1B [143], TLR5 [144], C7 [145] and CD163 [146] are thought to contribute to AD development and it has been reported to act as a potential biomarkers for AD treatment. IL1RAPL2 [147], GAD1 [148], EPHA5 [149], HTR1A [150], CADPS (calcium dependent secretion activator) [151], GABRG3 [152], LRFN5 [153] a...…”