GLRA1 – Hereditary Hyperekplexia

Hereditary hyperekplexia is a rare neuromotor disorder characterized by an exaggerated startle response and neonatal hypertonia. GLRA1 encodes the glycine receptor α1 subunit, which mediates inhibitory neurotransmission in the spinal cord and brainstem. Pathogenic variants in GLRA1 disrupt glycinergic inhibition, leading to disinhibition of brain‐stem reflexes and muscle rigidity. Both autosomal dominant and autosomal recessive inheritance patterns have been documented, reflecting variant‐specific effects on receptor function and expression.

Initial linkage and mutational analyses in four large families identified recurrent missense variants at Arg271, segregating with dominant hyperekplexia and reducing chloride conductance (PMID:8298642). A recessive case from a consanguineous pedigree revealed a homozygous deletion of exons 1–6 and complete loss of GLRA1 function, yet with compensatory glycinergic mechanisms preserving viability (PMID:8651283). Subsequent series of case reports and cohorts expanded the variant spectrum to include de novo missense changes (e.g., c.211A>T (p.Ile71Phe)), compound heterozygosity (c.569C>T (p.Thr190Met) + c.1246G>A (p.Asp416Asn)), and nonsense alleles.

To date, over 210 patients from both dominant and recessive families harbor GLRA1 variants (PMID:35636282). Reported variant classes encompass missense substitutions, nonsense/frameshift alleles, splice-site disruptions, and multi-exon deletions. c.690C>A (p.Tyr230Ter) recapitulates a null allele phenomenon in humans, contrasting with neonatal lethality in mouse oscillator models.

Functional studies have consistently demonstrated loss‐of‐function and dominant‐negative effects. Electrophysiological analyses reveal reduced glycine sensitivity, accelerated desensitization, and spontaneous channel activity for pathogenic alleles such as P250T (PMID:9920650). Trafficking assays show impaired surface expression of recessive mutants like S231R (PMID:11973623). The spasmodic mouse carrying Glra1 missense mutations phenocopies human startle disease, underscoring conserved pathogenic mechanisms (PMID:7920629).

No bona fide contradictory evidence has emerged; variant pathogenicity is corroborated by consistent clinical phenotypes, segregation, and concordant functional assays. Additional GLRA1‐interacting partners and animal models continue to elucidate pathomechanisms but exceed current ClinGen scoring thresholds.

Key Take‐home: GLRA1 variants cause definitive hyperekplexia through haploinsufficiency or dominant‐negative mechanisms, with robust genetic and functional evidence supporting molecular diagnosis, carrier screening, and targeted therapeutic strategies.

References

• American Journal of Human Genetics • 1996 • A GLRA1 null mutation in recessive hyperekplexia challenges the functional role of glycine receptors. PMID:8651283
• Nature Genetics • 1993 • Mutations in the alpha 1 subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. PMID:8298642
• Pediatric Neurology • 2022 • Hereditary Hyperekplexia: A New Family and a Systematic Review of GLRA1 Gene-Related Phenotypes. PMID:35636282
• 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
• 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

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