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Journal article
GLRB is the third major gene of effect in hyperekplexia
Human Molecular Genetics, Vol.22(5), pp.927-940
2013
Abstract
Glycinergic neurotransmission is a major inhibitory influence in the CNS and its disruption triggers a paediatric and adult startle disorder, hyperekplexia. The postsynaptic a1-subunit (GLRA1) of the inhibitory glycine receptor (GlyR) and the cognate presynaptic glycine transporter (SLC6A5/GlyT2) are well-established genes of effect in hyperekplexia. Nevertheless, 52% of cases (117 from 232) remain gene negative and unexplained. Ligand-gated heteropentameric GlyRs form chloride ion channels that contain the a1 and b-subunits (GLRB) in a 2a1:3b configuration and they form the predominant population of GlyRs in the postnatal and adult human brain, brainstem and spinal cord. We screened GLRB through 117 GLRA1- and SLC6A5-negative hyperekplexia patients using a multiplex-polymerase chain reaction and Sanger sequencing approach. The screening identified recessive and dominant GLRB variants in 12 unrelated hyperekplexia probands. This primarily yielded homozygous null mutations, with nonsense (n 5 3), small indel (n 5 1), a large 95 kb deletion (n 5 1), frameshifts (n 5 1) and one recurrent splicing variant found in four cases. A further three cases were found with two homozygous and one dominant GLRB missense mutations. We provide strong evidence for the pathogenicity of GLRB mutations using splicing assays, deletion mapping, cell-surface biotinylation, expression studies and molecular modelling. This study describes the definitive assignment of GLRB as the third major gene for hyperekplexia and impacts on the genetic stratification and biological causation of this neonatal/paediatric disorder. Driven principally by consanguineous homozygosity of GLRB mutations, the study reveals long-term additive phenotypic outcomes for affected cases such as severe apnoea attacks, learning difficulties and developmental delay.
Details
- Title
- GLRB is the third major gene of effect in hyperekplexia
- Authors
- S K Chung (Author)A Bode (Author)T D Cushion (Author)R H Thomas (Author)C Hunt (Author)S E Wood (Author)W O Pickrell (Author)C J G Drew (Author)S Yamashita (Author)R Shiang (Author)S Leiz (Author)A C Longardt (Author)V Raile (Author)B Weschke (Author)R D Puri (Author)I C Verma (Author)Robert J Harvey (Author) - UCL School of Pharmacy, United KingdomD D Ratnasinghe (Author)M Parker (Author)C Rittey (Author)Chris Masri (Author)Amira Masri (Author)Lokesh Lingappa (Author)Owain W Howell (Author)Jean-Francois Vanbellinghen (Author)Jonathon G Mullins (Author)Joseph W Lynch (Author)Mark I Rees (Author)
- Publication details
- Human Molecular Genetics, Vol.22(5), pp.927-940
- Publisher
- Oxford University Press
- Date published
- 2013
- DOI
- 10.1093/hmg/dds498
- ISSN
- 0964-6906
- Organisation Unit
- School of Health; School of Health and Sport Sciences - Legacy; Centre for Bioinnovation; School of Health and Behavioural Sciences - Legacy
- Language
- English
- Record Identifier
- 99451065702621
- Output Type
- Journal article
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- Web Of Science research areas
- Biochemistry & Molecular Biology
- Genetics & Heredity