Missense mutations as well as a null allele of the human glycine receptor alpha1 subunit gene GLRA1 result in the neurological disorder hyperekplexia [startle disease, stiff baby syndrome, Mendelian Inheritance in Man (MIM) #149400]. In a pedigree showing dominant transmission of hyperekplexia, we identified a novel point mutation C1128A of GLRA1. This mutation encodes an amino acid substitution (P250T) in the cytoplasmic loop linking transmembrane regions M1 and M2 of the mature alpha1 polypeptide. After recombinant expression, homomeric alpha1(P250T) subunit channels showed a strong reduction of maximum whole-cell chloride currents and an altered desensitization, consistent with a prolonged recovery from desensitization. Apparent glycine binding was less affected, yielding an approximately fivefold increase in Ki values. Topological analysis predicts that the substitution of proline 250 leads to the loss of an angular polypeptide structure, thereby destabilizing open channel conformations. Thus, the novel GLRA1 mutant allele P250T defines an intracellular determinant of glycine receptor channel gating.
Skeletal dysplasias, a heterogeneous group of bone growth disorders, can be detected by routine prenatal ultrasound examination. As it is difficult to make a specific diagnosis, prediction of prognosis is of importance for obstetric management. In order to specify diagnosis, radiological, pathological and molecular genetic examination are often required. Our report describes two cases of thanatophoric dysplasia with different fetal sonographic findings. The classical classification of type I and II seems to be ambiguous as, in both cases, the same mutation in the fibroblast growth factor receptor 3 gene was found. The importance of comprehensive multidisciplinary assessment is emphasized.
Alterations of glycine receptor alpha1 and beta subunit genes have been associated with hypertonic motor disorders in both mice and humans. Mutations in genes encoding other ligand- and voltage-gated ion channels have been identified in rare monogenic forms of idiopathic generalized epilepsies (IGE). We tested the hypothesis that allelic variants of the glycine receptor subunit genes, GLRA3 and GLRB, both localized on chromosome 4q, confer susceptibility to common subtypes of IGE. Mutation screening was carried out in index patients of 14 IGE families. No pathogenic mutation was found, but two intronic polymorphisms were detected in the GLRB gene, and four intronic, three exonic, and one 3'-UTR polymorphisms were identified for the GLRA3 gene. Subsequent screening for exonic and 3'-UTR polymorphisms in GLRA3 showed no statistical difference between a group of sporadic IGE patients (n = 104) and a control group (n = 141). The genotype frequencies for exonic and 3'-UTR polymorphisms in GLRA3 showed no statistically significant difference between IGE patients (n = 104) and an ethnically matched control group (n = 141). Thus, no association between IGE and alterations in GLRA3 or GLRB genes could be detected, indicating that both genes do not play a major causative role in the epileptogenesis of common IGE subtypes. Still, these novel single nucleotide polymorphisms may be useful markers for candidate gene analyses of other disorders.
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