Purine nucleoside phosphorylase deficiency – PNP gene

The purine nucleoside phosphorylase deficiency, or PNP deficiency, is an immunodeficiency characterized by the presence of a low number of T cells, whose function is to recognize and attack external invading agents to prevent infections. Some affected individuals also have a low number of B cells, which also help fight infections by producing antibodies (or immunoglobulins). The most severe form of this process is known as severe combined immunodeficiency (SCID), in which the affected individuals lack both T and B cells.

Individuals with PNP deficiency have repeated and persistent infections that can be very severe or life-threatening, and most often affect the sinuses and lungs. Usually, these infections are caused by "opportunistic" organisms, that is, those do not normally cause disease in people with a competent immune system. In addition, most individuals with this condition also have neurological problems, which may include developmental delay, intellectual disability, ataxia and spasticity. Individuals with this syndrome are also at an increased risk of developing autoimmune processes.

The PNP deficiency is due to mutations in the PNP (purine nucleoside phosphorylase) gene, located on the long arm of chromosome 14 (14q11.2), which encodes the purine nucleoside phosphorylase enzyme. This enzyme is found throughout the body, but is more active in lymphocytes. The purine nucleoside phosphorylase removes the waste molecules that are generated when the DNA breaks down. Specifically, it converts deoxinosine into hypoxanthine and deoxyguanosine into guanine.

More than 35 PNP gene mutations have been identified in individuals with purine nucleoside phosphorylase deficiency. Most of the mutations described consist of amino acid changes in the purine nucleoside phosphorylase enzyme that reduce or eliminate its activity. As a consequence, there is an excess of waste molecules that results in the accumulation of deoxyguanosine triphosphate (dGTP) at concentrations that are toxic to lymphocytes. T cells are particularly vulnerable to a toxic accumulation of dGTP, particularly immature T cells in the thymus. dGTP damages these cells and triggers their apoptosis. Lymphocyte deficiency causes vulnerability to severe infections. It is believed that damage to brain cells due to the accumulation of dGTP is the cause of neurological problems.

This disease is inherited with an autosomal recessive pattern, which means that both copies of the gene in each cell must have mutations for the alteration to be expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually do not show signs and symptoms of the disease. 

Tests performed in IVAMI: in IVAMI we perform the detection of mutations associated with the purine nucleoside phosphorylase deficiency, by means of the complete PCR amplification of the exons of the PNP gene, and their subsequent sequencing.

Recommended samples: non-coagulated blood obtained with EDTA for separation of blood leucocytes, or a card with a dried blood sample (IVAMI can mail the card to deposit the blood sample).