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., <i>MCPH1, WDR62</i>, and <i>ASPM</i>. Recently, mutations in the gene encoding the enzyme asparagine synthetase (<i>ASNS</i>) were associated to microcephaly and so far 24 different mutations in <i>ASNS</i> causing microcephaly have been described. In a family with two affected girls, we identified novel compound heterozygous variants in <i>ASNS</i> (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 <i>Escherichia coli</i> to <i>Homo sapiens</i> by glutamine. Protein modeling based on the known crystal structure of ASNS of <i>E. coli</i> 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 <i>ASNS</i>.