Novel Mutations in the Asparagine Synthetase Gene (ASNS) Associated With Microcephaly

Abstract

Microcephaly is a devastating condition defined by a small head and small brain compared to the age- and sex-matched population. Mutations in a number of different genes causative for microcephaly have been identified, e.g., MCPH1, WDR62, and ASPM. Recently, mutations in the gene encoding the enzyme asparagine synthetase (ASNS) were associated to microcephaly and so far 24 different mutations in ASNS causing microcephaly have been described. In a family with two affected girls, we identified novel compound heterozygous variants in ASNS (c.1165G > C, p.E389Q and c.601delA, p.M201Wfs∗28). The first mutation (E389Q) is a missense mutation resulting in the replacement of a glutamate residue evolutionary conserved from Escherichia coli to Homo sapiens by glutamine. Protein modeling based on the known crystal structure of ASNS of E. coli predicted a destabilization of the protein by E389Q. The second mutation (p.M201Wfs∗28) results in a premature stop codon after amino acid 227, thereby truncating more than half of the protein. The novel variants expand the growing list of microcephaly causing mutations in ASNS.

Asparagine Synthetase Deficiency with Intracranial Hemorrhage Can Mimic Molybdenum Cofactor Deficiency

“…All the described patients including this report share common clinical features 1-17 but with variable severity of the disease. Microcephaly was evident by the second trimester of pregnancy in our patient and those described by Seidahmed et al 6 and Schleinitz et al 13 At birth, the majority (80%) of ASD patients showed congenital microcephaly. Nevertheless, progressive microcephaly was reported in all patients.…”

Clinical outcomes of two patients with a novel pathogenic variant in ASNS: response to asparagine supplementation and review of the literature

“…This mutation is located in a highly conserved region of the C-terminal domain of the protein, which contains the ASNS domain (Fig. 2a, c, d) 2,14 . The variant was not found in the Genome Aggregation Database (http://gnomad.broadinstitute.org/), the Exome Aggregation Consortium (http://exac.broadinstitute.org/), or ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/).…”

“…The N-terminal domain contains the glutamine-binding pocket for the amidotransferase reaction, while the C-terminal domain is the ASNS domain and contains the ATP-binding site (Fig. 2c, d) 2,14 .…”

“…Patients with ASNSD present with features of hyperexcitability, which are apparent from their propensity for seizures, hyperreflexia, and hyperekplexia. As ASNS metabolically connects the four amino acids aspartate, asparagine, glutamate, and glutamine, the lack of asparagine and the dysregulation of the balance of excitatory neurotransmitters might contribute to neuronal damage and the enhanced excitability observed in affected patients 4,13,14 .…”

A novel compound heterozygous missense mutation in ASNS broadens the spectrum of asparagine synthetase deficiency

“…Cases of ASNSD reported from a variety of ethnic origins in the past few years (Abhyankar et al, 2018; Alfadhel et al, 2015; Ben‐Salem et al, 2015; Chen, Li, Wang, Chen, & Hong, 2019; Galada et al, 2018; Gataullina et al, 2016; Gupta et al, 2017; Palmer et al, 2015; Radha Rama Devi & Naushad, 2019; Ruzzo et al, 2013; Sacharow et al, 2018; Schleinitz et al, 2018; Seidahmed et al, 2016; Sprute et al, 2019; Sun et al, 2017; Yamamoto et al, 2017), have been summarized in Table 1 with information on nucleotide changes, amino acid changes, and the corresponding genotypes. ASNSD is considered ultrarare in China, with only one case reported in July 2019 (Chen et al, 2019).…”