Male proband with intractable seizures and a de novo start-codon-disrupting variant in GLUL

Abstract

Bi-allelic variants in GLUL, encoding glutamine synthetase and responsible for the conversion of glutamate to glutamine, are associated with a severe recessive disease due to glutamine deficiency. A dominant disease mechanism was recently reported in nine females, all with a de novo single-nucleotide variant within the start codon or the 5' UTR of GLUL that truncates 17 amino acids of the protein product, including its critical N-terminal degron sequence. This truncation results in a disorder of abnormal glutamine synthetase stability and manifests as a phenotype of severe developmental and epileptic encephalopathy. Here, we report the first male with a pathogenic de novo variant in the same critical region of GLUL, with a phenotype of refractory focal and generalized seizures, as well as developmental delays. We provide a detailed description of the disease course and treatment response.

Keywords: 5'UTR; GLUL; de novo; glutamine synthetase; seizures; start codon; start-loss.

Figure 1

GLUL locus and the impact of the c.-13-2A>G splice-disrupting 5'UTR variant (A) Schematic of GLUL locus. The location of the spice-disrupting variant in GLUL, c.-13-2A>G (red), in the 5′ UTR non-coding region upstream of exon 2 is depicted. Two degron sequences (yellow) fall between the canonical start codon Met1 (green) and the downstream alternative in-frame start codon Met18 (green) from which translation is reinitiated. Two RNA transcript isoforms are detected in the proband, 56% with normal splice pattern (purple) and 44% with aberrant splice pattern (orange) due to the c.-13-2A>G variant. The resulting protein is truncated at the 5′ end, removing the degron sequence required to regulate glutamine synthetase degradation by the proteasome and leading to impaired regulation of glutamine level. (B) Whole-blood RNA-seq analysis. The top shows RNA-seq from normalized GTEx blood samples. The middle shows whole-blood RNA-seq from the male RGP proband. Orange line depicts the novel splice junction created by the c.-13-2A>G variant, truncating exon 2. Purple lines depict known splice junctions. The bottom shows the MANE Select transcript (GenBank: NM_001033044, GenCode: ENST00000331872) with the positions of Met1 and Met18 indicated in green, where the first 26 bases are not present in 44% of the RNA-seq reads, consistent with a heterozygous casual variant. E, exon; Met, methionine.