A recent study provides new insights into the genetic underpinnings of a form of congenital microcephaly (Neuron 80, 429–441).

David Goldstein and his colleagues studied four families with a similar neurological syndrome consisting of microcephaly, intellectual disability and seizures. Using exome sequencing, the authors showed that the condition is caused by recessive mutations in the ASNS gene and identified three mutations (A6E, F362V and R550C) that lead to amino acid changes in the enzyme encoded by the gene, asparagine synthetase.

In vitro, the authors found that the A6E and F362V mutations led to reduced expression of asparagine synthetase, and the R550C mutation resulted in increased expression compared to the wild-type protein. Although the mechanism through which the R550C mutation acts is unclear, the authors suggest it might adversely affect the function of asparagine synthetase.

The researchers then analyzed gene-trap mice that contain an insertion in Asns that results in expression of Asns mRNA at ∼20% of its normal levels. Homozygous Asns gene-trap mice had smaller brains and larger lateral ventricles than wild-type controls and showed impaired memory. Interestingly, the gene-trap mice had a milder phenotype than affected humans with mutations in ASNS, with no evidence of seizures, but the generation of Asns-null mice in future studies may help the further investigation of this microcephaly syndrome.