New data published in Science points to a new mechanism to account for some cases of non-syndromic mental retardation: a mutation in the presynaptic protease neurotrypsin.

In non-syndromic mental retardation, there are no obvious neuroanatomical defects and no additional clinical features that could account for the abnormal phenotype. As the condition is so heterogeneous and there are no large pedigrees for its genetic analysis, we have limited information on the mechanisms that underlie this form of mental retardation. In the recent report, Molinari et al. studied a family in which four out of eight siblings have mental retardation, and carried out a genome-wide scan to identify any chromosomal regions of shared homozygosity in the affected children. They found a single region of chromosome 4q and honed in on the PRSS12 gene, which codes for neurotrypsin. After analysing this gene in the affected siblings, Molinari et al. discovered that they were homozygous for a 4-base-pair deletion that resulted in the production of a truncated protein. Moreover, the authors showed that a seemingly unrelated child, with a similar form of mental retardation, carried the same mutation.

Molinari et al. went on to investigate the pattern of neurotrypsin expression in the developing human brain. They found that the protein appears as early as 44 days of gestation, and is present in brainstem motor nuclei, cerebral cortex and hippocampus. Last, the authors analysed the subcellular distribution of neurotrypsin in the adult human brain and observed that, by contrast to most brain proteases, which are secreted and act extracellularly, neurotrypsin is located inside the presynaptic terminal.

Neurotrypsin is a poorly understood protease, the substrates and functions of which remain largely unknown. The data of Molinari et al. invite us to take a closer look at this enigmatic protein, not only in relation to non-syndromic mental retardation, but also regarding its role at the synapse. Their results also remind us that we need to reappraise the general involvement of proteolysis at the synapse on processes such as transmitter release and synaptic plasticity.