It isn't possible to measure potential energy because it has a (global) gauge symmetry. It's like trying to measure the height of a mountain - this could be the height above sea level, the height relative to the deepest sea trench, the height relative to the centre of the earth and so on. Any measurement can only measure the change in potential energy, and of course a change can be positive or negative i.e. the potential energy can increase or decrease.
This is my preferred way to understand the mass defect: start with the separate particles of combined mass $M$ at large distance. As the particles come together they accelerate due to the attractive force between them, so at the moment all the particles meet they have a high kinetic energy, $T$. To get the particles to form a bound state we need to remove this kinetic energy $T$, and that means taking out a mass of $m = T/c^2$ - hence the mass defect.
The total kinetic energy $T$ is just the negative of the potential energy change $\Delta U$ as the particles are brought from infinity into the bound state. It makes no difference what value you assign to $U(\infty)$ because all that matters is the change $\Delta U$.
Response to user52153's comment:
Suppose we start with two particles that attract each other. This could be an electron and proton, or two nucleons, though for convenience I'll assume they have same mass $m_0$. Start with the particles stationary and far enough apart that any interaction is negligable. Then the total energy is just:
$$ E_0 = 2m_0c^2 $$
Now let the particles move together under their mutual attraction. The attractive force will accelerate them, so some time later they will have a kinetic energy $T$. Since we haven't put any energy in or taken any energy out, the total energy must be unchanged so there must be a (negative) potential energy $U$ such that:
$$ 2m_0c^2 + T + U = 2m_0c^2 = E_0 $$
In other words $T + U = 0$ or $T = -U$, and remember that $U$ is a negative number.
At this point there is no mass deficit because the total energy is unchanged. Now user52153 proposes we use some mechanism to take the kinetic energy out of the system. It doesn't matter exactly how we do this - we use the kinetic energy to do work $W$ external to our system of two particles and we continue doing this work until $W = T$ so at this point the particles have been brought to rest. Because we have taken work $W = T$ out of the system the total energy is now:
$$ E_1 = 2m_0c^2 + U $$
The mass deficit $\Delta m = (E_0 - E_1)/c^2$ so:
$$ \Delta_m = \frac{E_0 - E_1}{c^2} = \frac{(2m_0c^2) - (2m_0c^2 + U)}{c^2} = -\frac{U}{c^2} $$
and because $U$ is a negative number that means $\Delta m$ is a positive number i.e. the total mass of the system has decreased.