Hyperekplexia (HE) is a rare inheritable neurologic disorder characterized by an exaggerated response to sudden stimuli, muscular rigidity, and hyperreflexia, leading to chronic injuries due to unprotected falls. All symptoms are present at birth but gradually decrease during the first year of life, although an exaggerated startle response remains during adulthood. Dysfunctional inhibitory neurotransmission by glycine (Gly) plays a central role in HE pathogene- sis. All patients with HE carry mutations in genes encoding either for 1 (GLYRA1) or (GLYRB) Gly receptor subunits, presynaptic Gly transporters (SLC6A5), or proteins involved in Gly receptor (GLYR) clustering, such as gephyrin (GPHN) and collybistin (ARHGEF9). Different GLYRA1 missense and nonsense mutations have been associated with autosomal dominant, autosomal recessive, and sporadic forms of HE. We investigated the functional consequences of a de novo GLYRA1 heterozygous nonsense mutation (S296X) in a 1-year-old boy. The mutation truncated the protein at codon 296 (S296X), within the TM3 domain. The functional consequences of this mutation were evaluated by biochemical and electrophysi- ologic techniques upon heterologous expression in HEK-293 cells. In conclusion, biochemical and electrophysiologic analyses suggest that GLYRA1 S296X sub- units impair GLYRA1 subunit function, thus representing the first description of a GLYRA1 het-erozygous nonsense mutation causing the startle phenotype by a dominant-negative mechanism.
|Stato di pubblicazione||Published - 2007|
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