SUMMARYMutations in NPRL3, one of three genes that encode proteins of the mTORC1-regulating GATOR1 complex, have recently been reported to cause cortical dysplasia with focal epilepsy. We have now analyzed a multiplex epilepsy family by whole exome sequencing and identified a frameshift mutation (NM_001077350.2; c.1522delG; p.E508Rfs*46) within exon 13 of NPRL3. This truncating mutation causes an epilepsy phenotype characterized by early childhood onset of mainly nocturnal frontal lobe epilepsy. The penetrance in our family was low (three affected out of six mutation carriers), compared to families with either ion channel-or DEPDC5-associated familial nocturnal frontal lobe epilepsy. The absence of apparent structural brain abnormalities suggests that mutations in NPRL3 are not necessarily associated with focal cortical dysplasia but might be able to cause epilepsy by different, yet unknown pathomechanisms. KEY WORDS: NPRL3, Nocturnal frontal lobe epilepsy, GATOR1, mTORC1 Pathway, Oldenburg.Frontal lobe epilepsies are a heterogeneous group of seizure disorders with a mostly polygenic or oligogenic background. Epilepsy families displaying monogenic inheritance are rare, but positional discovery of the causal genes has contributed significantly to our understanding of the molecular mechanisms underlying epileptogenesis. This is especially true for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), a disorder characterized by clusters of hypermotoric seizures arising during non-rapid eye movement (NREM) sleep. Associated cognitive or psychiatric symptoms are not uncommon in patients with ADNFLE, and are in some patients the predominant symptom. ADNFLE was originally thought to be a channelopathy because mutations were first identified in different nicotinic acetylcholine receptor (nAChR) subunit genes (CHRNA4, CHRNB2, and CHRNA2) and, later, in the potassium channel gene KCNT1.1-4 However, recent findings have shown that ADNFLE (and other types of focal epilepsy) are frequently caused by mutations in DEPDC5, a gene without obvious functional links to ion channels.5,6 DEPDC5 encodes a protein that is part of GATOR1, a complex of three proteins that acts as an important regulator of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1). mTORC1 regulates key cellular functions including protein synthesis, metabolism, and autophagy in response to environmental stimuli and stressors. The emerging importance of GATOR1 proteins for the pathogenesis of epilepsy has just been further supported by the identification of mutations in the two GATOR1 genes NPRL2 and NPRL3. NPRL3 mutations were initially found in six patients with focal epilepsy from whom four showed focal cortical dysplasia in MRI. 7 More recently a study identified NPRL3 and NPRL2 mutations in both sporadic and familial focal epilepsy. 8 Here we report a multiplex family that both
2q37.3 deletion syndrome belongs to the chromosomal 2q37 deletion spectrum which clinically resembles Albright hereditary osteodystrophy (AHO) syndrome. It is is mainly characterized by short stature, obesity, round face, brachydactyly type E, intellectual disability, behavioral problems, and variable intellectual deficits. Different from classical AHO syndrome, patients with 2q37 deletion syndrome lack renal parathyroid hormone resistance (pseudohypoparathyroidism) and soft tissue ossification. So far, deletion mapping or molecular breakpoint analyses of 2q37 have been performed in only few patients. Here, we report on 2 patients with 2q37.3 deletion syndrome. In both patients the breakpoint of the 5.5-Mb terminal microdeletion could be narrowed down to the same ∼200-kb interval on 2q37.3 by BAC-FISH and/or array-CGH. Flanking low-copy repeats may indicate a classical microdeletion syndrome genesis for the 2q37.3 microdeletion subgroup. Clinical evaluation revealed intellectual deficits and type E brachydactyly typical for classical AHO syndrome together with distinctive facial dysmorphisms not present in the former. Furthermore, one patient presented with schizophrenic psychosis, an observation that would be in accordance with previous reports about an association between schizophrenia susceptibility and an unknown gene within the chromosomal region 2q37.
BackgroundNon-coding single nucleotide polymorphisms within the nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4) are robustly associated with various neurological and behavioral phenotypes including schizophrenia, cognition and smoking. The most commonly associated polymorphisms are located in exon 5 and segregate as part of a haplotype. So far it is unknown if this haplotype is indeed functional, or if the observed associations are an indirect effect caused by linkage disequilibrium with not yet identified adjacent functional variants. We therefore analyzed the functional relevance of the exon 5 haplotype alleles.ResultsUsing voltage clamp experiments we were able to show that the CHRNA4 haplotype alleles differ with respect to their functional effects on receptor sensitivity including reversal of receptor sensitivity between low and high acetylcholine concentrations. The results indicate that underlying mechanisms might include differences in codon usage bias and changes in mRNA stability.ConclusionsOur data demonstrate that the complementary alleles of the CHRNA4 exon 5 haplotype are functionally relevant, and might therefore be causative for the above mentioned associations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-015-0204-1) contains supplementary material, which is available to authorized users.
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