Abstract
Nocturnal frontal lobe epilepsy has been historically considered a channelopathy caused by mutations in subunits of the neuronal nicotinic acetylcholine receptor or in a recently reported potassium channel. However, these mutations account for only a minority of patients, and the existence of at least a new locus for the disease has been demonstrated. In 2005, we detected two nucleotide variations in the promoter of the CRH gene coding for the corticotropin releasing hormone in 7 patients. These variations cosegregated with the disease and were demonstrated to alter the cellular levels of this hormone. Here, we report the identification in an Italian affected family of a novel missense mutation (hpreproCRH p.Pro30Arg) located in the region of the CRH coding for the protein pro-sequence. The mutation was detected in heterozygosity in the two affected individuals. In vitro assays demonstrated that this mutation results in reduced levels of protein secretion in the short time thus suggesting that mutated people could present an altered capability to respond immediately to stress agents.
Highlights
Nocturnal frontal lobe epilepsy (NFLE) is an idiopathic partial epilepsy with increased nocturnal instability, first described in 1994 [1]
The father, who was affected from REM sleep behaviour disorder (RBD) and was probably a carrier of the mutation, was dead it was impossible to verify the presence of the mutation
In this article we report a novel mutation (p.Pro30Arg) within the Corticotropinreleasing hormone (CRH) gene cosegregating with sleep disorders (i.e. ADNFLE and RBD) and detected in an Italian family
Summary
Nocturnal frontal lobe epilepsy (NFLE) is an idiopathic partial epilepsy with increased nocturnal instability, first described in 1994 [1]. In a group of NFLE patients we detected two nucleotide variations in the promoter region of the CRH gene (OMIM *122560) co-segregating with the disease and affecting the gene expression, suggesting a possible role in the disease pathogenesis [5,6]. This gene encodes for the Corticotropinreleasing hormone (CRH), a 41-amino acid peptide derived from a 196-amino acid preprohormone and widely distributed throughout the central nervous system [7,8,9]. CRH acts as a neurotransmitter or neuromodulator in extrahypothalamic circuits to integrate a multisystem response to stress that controls numerous behaviours such as locomotor activity, anxiety, food intake, sexual behaviour, sleep, arousal and learning [10,11,12]
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