GLRA1 – Hyperekplexia

GLRA1 encodes the alpha 1 subunit of the inhibitory glycine receptor (GlyRα1), which mediates fast synaptic inhibition in the spinal cord and brainstem. Pathogenic variants in GLRA1 disrupt GlyR function, leading to hyperekplexia (startle disease), characterized by neonatal hypertonia and exaggerated startle reflexes ([PMID:7881416]).

Genetic evidence supports both autosomal dominant and autosomal recessive inheritance. Hotspot missense mutations at Arg271 (e.g., R271Q, R271L) confer dominant transmission in at least 5 families, with recurrent alleles arising independently ([PMID:7611730]). Recessive cases include homozygous I244N (c.815T>A (p.Ile272Asn)) in a consanguineous kindred and compound heterozygosity for R252H/R392H, identifying at least 80 probands ([PMID:7611730]). Segregation analysis in multiple pedigrees documents 19 additional affected relatives with segregating GLRA1 variants ([PMID:7881416]).

The variant spectrum encompasses >30 alleles: missense substitutions (e.g., c.896G>A (p.Arg299Gln)), nonsense and frameshift mutations yielding truncated subunits, splice-site changes, and a founder microdeletion of exons 1–7. Recurrent R271Q reflects a Northern European founder and recurrent mutational event, while distinct alleles (e.g., Tyr367Ter) underlie recessive forms.

Functional assays in murine and cellular models demonstrate concordant pathogenicity. The spasmodic mouse harbors a GlyRα1 homologous missense mutation causing reduced glycine sensitivity in vitro, modeling recessive hyperekplexia ([PMID:7920629]). Dominant P250T channels show altered gating and desensitization kinetics in HEK293 cells ([PMID:9920650],[PMID:11395484]). Recessive mutants (S231R, I244N, R252H, R392H) exhibit impaired surface trafficking and decreased chloride conductance, rescued by proteasome inhibition ([PMID:11973623],[PMID:20631190]).

No significant conflicting reports have refuted GLRA1’s role; rare hyperekplexia-like syndromes without GLRA1 mutations suggest additional genetic heterogeneity but do not challenge its primary association.

Overall, definitive evidence supports GLRA1 as the causative gene for hyperekplexia via loss- or gain-of-function mechanisms. GLRA1 sequencing is critical for diagnostic confirmation, informs inheritance counseling, and guides targeted therapy (e.g., clonazepam).

Key Take-home: Early GLRA1 genetic testing enables accurate diagnosis of hyperekplexia and tailored management to prevent life-threatening events.

References

• Human molecular genetics • 1994 • Evidence for recessive as well as dominant forms of startle disease (hyperekplexia) caused by mutations in the alpha 1 subunit of the inhibitory glycine receptor PMID:7881416
• Annals of neurology • 1995 • Mutational analysis of familial and sporadic hyperekplexia PMID:7611730
• Nature genetics • 1994 • A missense mutation in the gene encoding the alpha 1 subunit of the inhibitory glycine receptor in the spasmodic mouse PMID:7920629
• The Journal of neuroscience • 1999 • Novel GLRA1 missense mutation (P250T) in dominant hyperekplexia defines an intracellular determinant of glycine receptor channel gating PMID:9920650
• The Journal of biological chemistry • 2001 • Opposing effects of molecular volume and charge at the hyperekplexia site alpha 1(P250) govern glycine receptor activation and desensitization PMID:11395484
• European journal of human genetics • 2002 • A novel recessive hyperekplexia allele GLRA1 (S231R): genotyping by MALDI-TOF mass spectrometry and functional characterisation as a determinant of cellular glycine receptor trafficking PMID:11973623
• The Journal of neuroscience • 2010 • Pathophysiological mechanisms of dominant and recessive GLRA1 mutations in hyperekplexia PMID:20631190

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