Naxos disease is a rare inherited defect of the air shaft resulting in sparse and dystrophic hair. The clinical picture consists of an associated triad of woolly hair, thickened palms and soles (keratoderma) and heart involvement. The hair phenotype is unique, characterized by woolly, curly, rough and light colored scalp hair and sparse eyebrows. Affected individuals suffer at young age from severe psychological and social disability and later also develop a severe heart disease that may end with arrhythmia and premature sudden death. Recently, the gene for this disease was mapped to chromosome 17 in Greek families. The exact molecular defect has not been identified yet. However, the associated skin and heart involvement suggest that the disease may not result solely from an abnormality in a structural protein but from proteins that may be involved in intercellular communication. The recent findings of the genes causing erythrokeratoderma variabilis as well as palmoplantar keratoderma and deafness have proven the importance cell-communication proteins in skin integrity. We have identified additional 2 large families in Israel and have already obtained their consent to participate in this study. We obtained DNA from most members of these families. We plan to complete the DNA collection from these families and also from several Ecuadorian families suffering from the same disease. A linkage study performed at our lab in these 2 families to the keratin cluster in chromosomes l7 and 12 failed to identify linkage. Therefore, we plan to test linkage in these families to other known areas associated with keratodermas. If no linkage is found, we plan to screen for mutations in plakoglibin, a protein involved in hair, skin and heart development and found in the previously described linked-region of chromosome 17. If the above studies fail, we will initiate a whole genome search. Power calculations suggest that we can anticipate finding the gene/s causing Naxos disease in our families. The significance of this study can be divided into two categories. For the patients themselves, understanding the genetics of the disease will permit more precise diagnosis as well as premarital and prenatal genetic counseling. Furthermore, Naxos disease has extreme importance also from the cardiac point of view and early diagnosis may lead to proper and early treatment, which may be life saving. On a more general level, identification of these genes, locating the specific mutations and correlation with clinical findings invariably increases our understanding of normal hair physiology and of other related diseases. In the future, this improved understanding may be translated into novel therapeutic approaches to the treatment of this and other hair diseases.
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