Keratoderma with woolly hair – JUP, DSP, DSC2 and KANK2 genes

Keratoderma with woolly hair includes a group of related diseases that affect the skin and hair, manifesting signs and symptoms that overlap, and in many cases affected people are at greater risk of manifesting life-threatening heart problems. Affected people have unusually thick, dry, fine and well curly hair. In addition, hair is also scarce in some cases. The texture of woolly hair normally affects only the hair of the scalp and is present from birth. Other signs and symptoms include palmoplantar keratoderma and cardiomyopathy. Unlike the other characteristics of this disease, the signs and symptoms of cardiomyopathy may not appear until adolescence or later. Complications of cardiomyopathy may include arrhythmia, heart failure and sudden death.

Recently, this disease has been classified into four types, based on the underlying genetic cause. Type I, also known as Naxos disease, is characterized by palmoplantar keratoderma, woolly hair, and a form of cardiomyopathy called arrhythmogenic right ventricular cardiomyopathy (ARVC). Type II, also known as Carvajal syndrome, manifest alterations in hair and skin similar to type I, but is related to a different form of cardiomyopathy, called dilated cardiomyopathy of the left ventricle. Type III also has signs and symptoms similar to those of type I, including ARVC, although hair and skin abnormalities are often milder. On the other hand, type IV is characterized by palmoplantar keratoderma and woolly and thin hair, as well as abnormal nails. Unlike types I, II and III, type IV does not appear to cause cardiomyopathy.

This process is due to mutations in the JUP (junction plakoglobin), DSP (desmoplakin), DSC2 (desmocollin 2), and KANK2 (KN motif and ankyrin repeat domains 2) genes. The JUP, DSP and DSC2 genes encode components of desmosomes, which are found in the membrane that surrounds certain cells, including skin and heart muscle cells. These structures contribute to cell adhesion, which provides resistance and stability to tissues. In addition, they play a role in other important cellular functions, including chemical signaling pathways, cell differentiation and apoptosis. For its part, the KANK2 gene, unlike the JUP, DSP and DSC2 genes, encodes a protein that regulates steroid receptor coactivators (SRCs), whose function is to help activate certain genes. SRC plays an important role in tissues throughout the body, including the skin.

The DSC2 gene, located on the long arm of chromosome 18 (18q12.1), encodes the desmocolin-2 protein. This protein is found in many tissues, although it seems to be particularly important in the heart and skin muscle. Desmocolin-2 is an important component of desmosomes. Mutations identified in the DSC2 gene related to type III of this disease result in the synthesis of an abnormal desmocolin-2 protein that alters the structure of desmosomes, preventing cells from adhering to each other effectively. It is believed that poor connections between cells make the skin, hair and heart muscle more fragile. Over time, these tissues become damaged, which probably underlies the skin, hair and heart problems that occur in people with keratoderma with woolly hair type III. In addition, it is likely that abnormal cell signaling may also contribute to cardiomyopathy in people with this disease.

The DSP gene, located on the short arm of chromosome 6 (6p24.3), encodes the desmoplakin protein. This protein is found mainly in heart and skin cells, where it is an important component of desmosomes. Mutations identified in the DSP gene in people affected by type II of this process, lead to the synthesis of an abnormally short version of the desmoplakin protein. The abnormal protein alters the structure of desmosomes, which makes cell adhesion difficult. Poor connections between cells make the skin, hair and heart muscle more fragile, which underlies the skin, hair, and heart problems that occur in type II keratoderma with woolly hair. It is believed that abnormal cell signaling may also contribute to cardiomyopathy in affected people.

The JUP gene, located on the long arm of chromosome 17 (17q21.2), encodes the plakoglobin protein. This protein is found mainly in the heart and skin cells, where it is part of the adherent junctions and desmosomes. Both structures provide resistance and stability to the tissues. In addition, plakoglobin also plays a role in signaling inside cells as part of the Wnt pathway. Wnt signaling controls the activity of certain genes and regulates interactions between cells. This signaling pathway is involved in many aspects of development, including the normal development of the heart, skin and hair. The mutations described result in the synthesis of an abnormally short version of the plakoglobin protein, which cannot interact properly with other desmosomal proteins, which alters the structure of desmosomes. As a consequence, the cells don’t adhere to each other effectively. These poor connections between the cells make the skin, hair and heart muscle more fragile. Over time these tissues become damaged, which causes skin, hair and heart problems that occur in people with woolly type I keratoderma. In addition, these mutations are likely to impair Wnt signaling, which it seems to cause heart muscle cells to be replaced with fat cells over time. This abnormal signaling can influence the development of ARVC in affected individuals.

The KANK2 gene, located on the short arm of chromosome 19 (19p13.2), encodes a protein called the SRC interaction protein (SIP). SIP regulates steroid receptor coactivators (SRCs), which play a critical role in the activation of certain genes. Inside the cells, SIP aggregates bind to SRC in the cytoplasm. With this, SIP prevents these proteins from entering the nucleus to activate genes. In this way, SIP helps control the activity of genes. SIP is found in many organs and tissues, including the skin and kidneys. However, little is known about its specific functions in various parts of the body. At least 1 mutation in the KANK2 gene has been identified in people with keratoderma with woolly hair type IV. The identified mutation replaces the amino acid alanine with the amino acid valine at position 670 in SIP (Ala670Val or A670V). It is believed that this mutation affects a region of SIP that is essential for its interaction with SRC, which ultimately causes changes in gene activity. However, it is not clear how this mutation affects hair and skin growth, or why its effects appear to be limited to these tissues.

Most cases of keratoderma with woolly hair are 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 keratoderma with woolly hair, by means of the complete PCR amplification of the exons of the JUP, DSP, DSC2 and KANK2 genes, 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).