SERPINI1

The SERPINI1 gene provides instructions for making a protein called neuroserpin, which is a type of serpin protein. Serpins, which are also known as serine protease inhibitors, help control several types of chemical reactions by inhibiting certain enzymes. Neuroserpin inhibits the activity of an enzyme called tissue plasminogen activator (tPA), which plays a role in cell movement (migration), blood clotting, and inflammation.

As its name suggests, neuroserpin is involved in the development and function of the nervous system. This protein helps control the growth of nerve cells, particularly specialized extensions called axons that are required for the transmission of nerve impulses. Neuroserpin also plays a role in the development of connections between nerve cells (synapses), where cell-to-cell communication occurs. Synapses can change and adapt over time in response to experience (a characteristic called synaptic plasticity). Neuroserpin helps regulate synaptic plasticity, which suggests that it may be important for learning and memory.

familial encephalopathy with neuroserpin inclusion bodies - caused by mutations in the SERPINI1 gene

At least four mutations in the SERPINI1 gene have been identified in families with familial encephalopathy with neuroserpin inclusion bodies. Each of these mutations changes a single protein building block (amino acid) used to make the neuroserpin protein. SERPINI1 mutations result in the production of an abnormally shaped, unstable version of neuroserpin. Abnormal neuroserpin proteins can attach to one another and form clumps (called neuroserpin inclusion bodies or Collins bodies) within nerve cells. These clumps disrupt the cells' normal functioning and ultimately lead to cell death. Progressive dementia results from this gradual loss of nerve cells in certain parts of the brain. Additionally, SERPINI1 mutations reduce or eliminate the ability of neuroserpin to inhibit tPA in nerve cells. Researchers believe that unchecked activity of tPA may also contribute to the signs and symptoms of this condition.

The severity and age of onset of this disorder vary by mutation and are correlated with the number of Collins bodies present in nerve cells. One mutation, known as neuroserpin Syracuse, is associated with a moderate form of the disorder that causes a progressive decline in intellectual functioning beginning in a person's forties or fifties. This genetic change replaces the amino acid serine with the amino acid proline at position 49 in the neuroserpin protein (written as Ser49Pro or S49P).

Other SERPINI1 mutations cause a more severe form of the disorder that is characterized by seizures and episodes of sudden, involuntary muscle jerking or twitching (myoclonus) in addition to dementia. These signs can appear as early as a person's teens. One of these severe mutations, called neuroserpin Portland, replaces the amino acid serine with the amino acid arginine at position 52 in the neuroserpin protein (written as Ser52Arg or S52R). Another severe mutation replaces the amino acid glycine with the amino acid glutamic acid at protein position 392 (written as Gly392Glu or G392E). Children with this genetic change experience a very severe form of the disorder that includes generalized seizures, uncontrollable muscle jerks, and delayed development.