Nonbullous congenital ichthyosiform erythroderma - ABCA12, ALOX12B and ALOXE3 genes

Nonbullous congenital ichthyosiform erythroderma (NBCIE), or congenital ichthyosiform erythroderma (CIE), is a disease that primarily affects the skin. Some affected children are born with a membrane that usually detaches during the first weeks of life. Individuals with this disease have skin covered with fine white scales and erythema. In addition, some affected people manifest the eyelids and lips turned outward, palmoplantar keratoderma, nail dystrophy, and anhydrosis, and alopecia in severe cases. Moreover, newborns with NBCIE may have infections, dehydration and respiratory problems at an early age.

Most cases of NBCIE are due to mutations in the ABCA12, ALOX12B, and ALOXE3 genes. Mutations in other genes, including the CASP14, CERS3, CYP4F22, NIPAL4 and PNPLA1 genes, have been identified only in a small percentage of cases. In some people with NBCIE the cause of the disease is unknown.

The ABCA12 (ATP binding cassette subfamily A member 12) gene, located on the long arm of chromosome 2 (2q35), encodes a transporter protein known as the ATP-binding cassette (ABC). ABC transporter proteins transport many types of molecules through cell membranes. In particular, ABCA12 protein plays an important role in the transport of lipids in the cells that form the epidermis. This lipid transport seems to be essential for normal skin development. ABCA12 protein is also found in other tissues, including testicles, placenta, lung, stomach, fetal brain and liver.

At least 20 mutations in the ABCA12 gene have been identified in individuals affected by the disease. Most of the mutations described consist of individual amino acid changes in the ABCA12 protein. These mutations probably result in the synthesis of a protein with reduced function, which impairs lipid transport and the formation of lipid layers inside the epidermis. Problems with this protective barrier are the cause of skin abnormalities and other disease characteristics.

The ALOX12B (arachidonate 12-lipoxygenase, 12R type) and ALOXE3 (arachidonate lipoxygenase 3) genes, both located on the short arm of chromosome 17 (17p13.1), encode proteins found in the epidermis (12R-LOX and eLOX3, respectively). These enzymes are part of a family of enzymes called lipoxygenases. Most of these enzymes help to add an oxygen molecule to a fatty acid (arachidonic acid). The addition of an oxygen molecule to arachidonic acid results in fatty acid hydroperoxides, which can be transformed into a variety of signaling molecules. Specifically, the 12R-LOX and eLOX3 enzymes help to add an oxygen molecule to arachidonic acid, to form a substance that is subsequently converted to a signaling molecule involved in the proliferation and differentiation of skin cells. It is believed that both enzymes play a role in the formation and maintenance of the fat layer of the cells that form the epidermis. The epidermis helps prevent water loss, regulates body temperature and protects against infections.

More than 55 mutations in the ALOX12B gene and at least 20 mutations in the ALOXE3 gene have been identified in people with NBCIE. Most of these mutations change amino acids in the 12R-LOX or eLOX3 enzyme. Other mutations result in the synthesis of a non-functional 12R-LOX or eLOX3 enzyme, which alters the formation of the lipid membrane inside the cells of the epidermis. Skin abnormalities associated with NBCIE deteriorate this protective barrier, which makes it difficult for affected children to control water loss, regulate body temperature and fight infections. Mutations in the ALOX12B and ALOXE3 genes are responsible for most cases of NBCIE.

This disease is inherited with an autosomal recessive pattern, that is, 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 nonbullous congenital ichthyosiform erythroderma (NBCIE), by means of the complete PCR amplification of the exons of the ABCA12, ALOX12B and ALOXE3 genes, respectively, and their subsequent sequencing.

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