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Hyperekplexia caused by dominant-negative suppression of glyra1 function
- Publication Year :
- 2007
- Publisher :
- Lippincott, Williams & Wilkins:530 Walnut Street:Philadelphia, PA 19106:(800)638-3030, (301)223-2300, EMAIL: orders@lww.com, INTERNET: http://www.lww.com, Fax: (301)223-2320, (301)223-2320, 2007.
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Abstract
- Hyperekplexia (HE; startle disease; OMIM#149400) 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 decline during the first year of life, although an exaggerated startle response remains during adulthood.1 Dysfunctional inhibitory neurotransmission by glycine (Gly) plays a central role in HE pathogenesis. All patients with HE carry mutations in genes encoding either for α1 (GLYRA1) or β (GLYRB) Gly receptor subunits, presynaptic Gly transporters (SLC6A5), or proteins involved in Gly receptor (GLYR) clustering, such as gephyrin (GPHN) and collybistin (ARHGEF9).1,2 GLYRA1 subunits interact in a heteropentameric complex with homologous β subunits (3α12β). Each subunit comprises an extracellular N-terminus, four α-helical transmembrane segments (TM1 to TM4), and an extracellular C-terminus; TM2 segments are thought to align the Cl− selective pore.1 Different GLYRA1 missense and nonsense mutations have been associated with autosomal dominant, autosomal recessive, and sporadic forms of HE. Missense mutations may show incomplete penetrance and impair channel gating, trafficking, and stability.3 Nonsense mutations have been reported only in recessive cases, in compound heterozygosity with a missense mutation, or in homozygosity in the offspring of consanguineous nonaffected parents and appear unable to cause the startle phenotype in heterozygosis.4,5 A recessive form of HE linked to a GLYRA1 null allele has been described,6 suggesting a nonpathogenic role for haplotype insufficiency. In this study, we investigated the functional consequences of a de novo …
- Subjects :
- Male
medicine.medical_specialty
Subunit
Reflex, Startle
Nonsense mutation
Compound heterozygosity
Gene
Receptors, Glycine
Internal medicine
medicine
Missense mutation
Humans
Glycine Receptor
Hyperekplexia
Glycine receptor
Nervous System Disease
Genetics
Startle Disease
Neuroscience (all)
Gephyrin
biology
Infant
Penetrance
Pedigree
Endocrinology
NON PREVISTO DA NORME REDAZIONALI (“NEUROLOGY”)
Codon, Nonsense
Mutation
biology.protein
Neurology (clinical)
medicine.symptom
Nervous System Diseases
Collybistin
Human
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....35c076af9979f965f3a46e5280c72d0e