Abstract
BACKGROUND: The pathogenesis of hereditary hyperekplexia is thought to involve abnormalities in the glycinergic neurotransmission system, the most of mutations reported in GLRA1. This gene encodes the glycine receptor α1 subunit, which has an extracellular domain (ECD) and a transmembrane domain (TMD) with 4 α-helices (TM1-TM4). CASE PRESENTATION: We investigated the genetic cause of hyperekplexia in a Chinese family with one affected member. Whole-exome sequencing of the 5 candidate genes was performed on the proband patient, and direct sequencing was performed to validate and confirm the detected mutation in other family members. We also review and analyse all reported GLRA1 mutations. The proband had a compound heterozygous GLRA1 mutation that comprised 2 novel GLRA1 missense mutations, C.569C > T (p.T190 M) from the mother and C.1270G > A (p.D424N) from the father. SIFT, Polyphen-2 and MutationTaster analysis identified the mutations as disease-causing, but the parents had no signs of hyperekplexia. The p.T190 M mutation is located in the ECD, while p.D424N is located in TM4. CONCLUSIONS: Our findings contribute to a growing list GLRA1 mutations associated with hyperekplexia and provide new insights into correlations between phenotype and GLRA1 mutations. Some recessive mutations can induce hyperekplexia in combination with other recessive GLRA1 mutations. Mutations in the ECD, TM1, TM1-TM2 loop, TM3, TM3-TM4 loop and TM4 are more often recessive and part of a compound mutation, while those in TM2 and the TM2-TM3 loop are more likely to be dominant hereditary mutations.